Lipids and Lipid-Binding Proteinsin Selective Autophagy

Review
YJMBI-66165; No. of pages: 25; 4C:
Lipids and Lipid-Binding Proteins

in Selective Autophagy
Laura R. de la Ballina, Michael J. Munson and Anne Simonsen

Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Correspondence to Anne Simonsen: anne.simonsen@medisin.uio.no

https://doi.org/10.1016/j.jmb.2019.05.051
Abstract
Eukaryotic cells have the capacity to degrade intracellular components through a lysosomal degradation
pathway called macroautophagy (henceforth referred to as autophagy) in which superfluous or damaged
cytosolic entities are engulfed and separated from the rest of the cell constituents into double membraned
vesicles known as autophagosomes. Autophagosomes then fuse with endosomes and lysosomes, where cargo
is broken down into basic building blocks that are released to the cytoplasm for the cell to reuse. Autophagic
degradation can target either cytoplasmic material in bulk (non-selective autophagy) or particular cargo in what is
called selective autophagy. Proper autophagic turnover requires the orchestrated participation of several players
that need to be tightly and temporally coordinated. Whereas a large number of autophagy-related (ATG) proteins
have been identified and their functions and regulation are starting to be understood, there is substantially less
knowledge regarding the specific lipids constituting the autophagic membranes as well as their role in initiating,
enabling or regulating the autophagic process. This review focuses on lipids and their corresponding binding
proteins that are crucial in the process of selective autophagy.
© 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction Autophagy has been extensively studied over the

last decades. Original pioneering screens identified
Upon specific stresses (such as starvation, oxida- autophagy-related (ATG) genes in yeast and re-
tive stress, hypoxia or ER stress) the autophagy search over the following years has led to the
machinery assembles on pre-existing membranes to identification of mammalian orthologs (or expansion
form de novo cup-shaped membrane structures paralogs, as in the case of the ATG8 family proteins)
called phagophores [1] . Owing to membrane con- and the molecular decipherment of the roles of such
tributions from different sources [2], phagophores gene products in many relevant steps of the pathway
expand until engulfment of their preferred cargo (in [5] . Thus, our current understanding of autophagy
selective autophagy) or bulk cytoplasm (in the case revolves mostly around ATG proteins (in this review,
of starvation-induced autophagy) is achieved. we will generally refer to mammalian ATG proteins, if
Sealed phagophores form double-membrane autop- mentioning yeast orthologs it will be clearly stated
hagosomes responsible for cargo delivery to lyso- and designated as Atg). A subset of these proteins
somes, where low pH and lysosomal hydrolases assemble into functional complexes that constitute
cause degradation of cargo into basic components the core autophagy machinery (essential for cargo
that can be reused by the cell to survive the stress [3] sequestration and lysosomal delivery, both in bulk
(Fig. 1) . Autophagy also serves a housekeeping and selective autophagy): (i) the Unc51-like kinase
function under basal conditions to maintain cell (ULK) complex, a serine/threonine kinase complex
homeostasis, and concomitantly, malfunctioning of that includes ULK1 and associated partners ATG13,
the pathway has been linked to several diseases [4] . RB1-inducible coiled-coil protein 1 (RB1CC1, also
0022-2836/© 2019 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/). Journal of Molecular Biology (xxxx) xx, xxx
Please cite this article as: L. R. de la Ballina, M. J. Munson and A. Simonsen, Lipids and Lipid-Binding Proteins in Selective
Autophagy, Journal of Molecular Biology, https://doi.org/10.1016/j.jmb.2019.05.051
2 Lipid-binding proteins in selective autophagy
Fig. 1. Macroautophagy overview. Depiction of autophagosome formation, cargo recruitment and delivery to lysosomes
in bulk and selective autophagy. Lysosomal degradation, autophagic lysosome reformation (ALR) and the general
principle of autophagy receptors (LIR, LC3-interacting region; UBA, ubiquitin-associated domain) are indicated (see Fig. 3
for details on specific lipid-binding protein mechanisms in selective autophagy). ULK complex is essential for recruitment of
PIK3C3 to omegasomes, leading to synthesis of PtdIns3P and recruitment of WIPI2. In turn, WIPI2 recruits the ATG12–
ATG5–ATG16L1 complex, enabling lipidation of ATG8 family proteins. ATG2 is involved in lipid transfer activity at ER-
phagosome contact sites. ATG9 vesicles contribute as membrane input for phagophore expansion. During
autophagosome maturation, ATG4 removes ATG8 family proteins from the cytosolic interface of autophagosomes. At
the mature autophagosome, ATG12–ATG5–TECPR1 is recruited to facilitate lysosome fusion. PtdIns involved at the
different steps of the pathway are marked. For details regarding the specific functions and kinases/phosphatases
mediating conversion (indicated with an arrow), refer to section “Phosphoinositides” in the text.
known as FIP200) and ATG101; (ii) the autophagy little is known about the role and source of lipids
specific class III phosphatidylinositol 3-kinase involved in autophagy, their interaction with the
VPS34 (PIK3C3) complex I, which comprises autophagic protein machinery or the regulation
VPS34, Beclin 1 (BECN1), the pseudokinase p150 between protein and lipid components. Still today
(VPS15/PIK3R4) and ATG14L1; (iii) the ATG9 (only the origin and composition of autophagosomes
transmembrane core ATG protein) cycling system remain largely unknown [1,6] . The lack of informa-
together with the complex formed by WD repeat tion is due in part to technical difficulties encountered
domain phosphoinositide-interacting (WIPI) proteins in determining the phospholipid molecular composi-
and their partner ATG2; and (iv) two ubiquitin-like tion of subcellular membranes by traditional tech-
conjugation complexes, one [ATG7 (E1), ATG10 niques. It is known, however, that the presence of
(E2)] that conjugates ATG12 to ATG5, which later proteins is relatively scarce in autophagic mem-
associates to ATG16L1, and another one that branes [7,8] , suggesting that the protein pool of
facilitates covalent attachment of ATG8 family autophagosome membranes is limited to the mini-
members (see below) to PE through the action of mal components required for cargo sequestration
ATG7 (E1), ATG3 (E2) and the ATG12–ATG5– and delivery, but also emphasizing the central role
ATG16L1 complex (E3). that lipids play in autophagy.
This core autophagy machinery functions at the In selective autophagy, membrane recruitment
interface between the cytoplasm and the membrane and expansion are cargo-dependent. Autophagy
of several cellular compartments. However, very receptors facilitate expansion of the
Lipid-binding proteins in selective autophagy 3
autophagosome membrane around the cargo (e.g., polar head and charge [34]. Glycerophospholipids
damaged mitochondria, invading pathogens, ag- are the main structural lipids of eukaryotic mem-
gregated proteins) by simultaneously binding the branes that are distinguishable primarily by head-
cargo, FIP200 and ATG8 family proteins in the group: phosphatidylcholine (PC) and
membrane [9–11]. The high avidity of cargo phosphatidylethanolamine (PE) are the most abun-
receptors to membrane-localized ATG8 family dant ones (40%–50% and ~ 17%–25% of total
proteins excludes any non-targeted material from phospholipids, respectively), whereas phosphatidic
sequestration within autophagosomes [12]. acid (PA), phosphatidylserine (PS) and phos-
There are many types of selective autophagy phatidylinositol (PI), despite being less abundant
likely functioning under different specific mecha- than PC or PE, are still major components of
nisms of action, which remain broadly unknown. membranes [35] . Phosphoinositides (PtdIns; phos-
Whereas amino acid starvation is the stressor most phorylated derivatives of PI) are on the contrary rare
widely utilized for induction of autophagy [13], with lipids (b 1% of phospholipids) but display central
well-established protocols and results confirmed by roles in signaling and membrane trafficking path-
different research groups, this is not the case for ways [36,37] . Sphingolipids [namely, polar phos-
selective autophagy, where studies are more pholipid sphingomyelin (SM) and
fragmented and usually focusing on specific steps glycosphingolipids (GSLs)] constitute another
of the autophagic process. Thus, little is yet known class of membrane structural lipids [38] . Along
about lipids and binding proteins in selective with glycerol-based phospholipids and ceramide
autophagy, and we will therefore start this review (Cer)-based sphingolipids, eukaryotic membranes
with a description of lipid-binding proteins in bulk invariably contain sterols (ergosterol in yeast and
autophagy before centring our focus on the selec- cholesterol in mammals), the major non-polar lipids
tive autophagic processes. of cells that confer fluidity to membranes [38] (Fig.
2). The role lipid composition plays in autophagic
membranes remains elusive, as well as the possi-
Autophagy Is a Membrane-Driven Cata- ble functional consequences of the presence of
bolic Pathway specific lipids.
Autophagy relies heavily upon membrane dy-

namics, with most steps in the process depending Lipid-Binding Proteins
on complex sequences of membrane remodeling
and trafficking events [14] . In brief, under starvation Lipids are relevant regulators of cellular stabiliza-
conditions, the ULK1 complex is relieved from tion and signaling [34], as such, changes in their
inhibitory phosphorylation by the mammalian target composition, distribution or trafficking have pro-
of rapamycin complex 1 (mTORC1) and gets found implications in autophagy [14,39] . Such
recruited to the phagophore nucleation site effects are either mediated by lipid-binding protein
[15,16], where it phosphorylates the PIK3C3 com- effectors or by lipids themselves and their influence
plex I [17,18] that, in turn, generates on membrane properties. While transmembrane
phosphatidylinositol 3-phosphate (PtdIns3P) on domains of integral proteins interact preferentially
the target membrane [19] . The PtdIns3P effector with specific lipids, membrane-distinct lipid signa-
WIPI2b is then recruited and enables LC3 lipidation tures determine the peripheral proteins that will be
to the phagophore by direct binding to ATG16L1 of recruited. Such protein recruitment can be deter-
the ATG12–ATG5–ATG16L1 complex [20,21]. mined by physical properties of membranes (e.g.,
Transient interactions with the ATG9-positive ves- flatness/curvature, membrane thickness or fluidity),
icles (originating from sources such as recycling their chemical characteristics (e.g., composition or
endosomes, plasma membrane, ER or Golgi charge) or by direct interaction between membrane
[22–26]) and the lipid transfer action of ATG2 lipids and proteins in a lock and key-like manner,
working in collaboration with WIPI proteins facilitated by specific protein lipid-binding domains.
[27–29] mediate phagophore expansion. Final Below we discuss examples of these processes in
closure of autophagosomes is likely facilitated by relation to autophagy.
the ESCRT machinery [30,31], with CHMP2A
playing a prominent role [32]. During autophago- Membrane lipid composition
some maturation, cytosolic accessible LC3 is
cleaved from the membrane through the action of Variations in lipid composition can severely
ATG4 [33] before fusion with lysosomes. affect the physicochemical properties of mem-
In eukaryotic cells, membranes are organized as branes. The size of the polar head, along with
lipid bilayers typically composed of hundreds of the space occupied by the acyl chains give the
lipids with varying length of hydrocarbon chains, corresponding lipid an overall cylindrical or conical
degree of unsaturation, chemical properties of the shape [40] (Fig. 2) . Specific lipid signatures
provide membranes with unique identities and negatively regulate the activity of phospholipase
functions. Thus, changes in the composition of a D1 (PLD1). Loss of HS1BP3 via siRNA-mediated
lipid bilayer can therefore potentially promote or depletion leads to an estimated 2-fold increase in
hinder the progression of autophagy. A prime PA and this in turn enhances autophagic flux [41] .
example of this can be seen with the protein Both HS1BP3 and PLD1 contain PX domains, and
HCLS1 binding protein 3 (HS1BP3) that is able to HS1BP3 was found to negatively regulate
localization of PLD1 to ATG16L1-containing mem- docking platforms for recruitment of the autophagy
branes. It is not completely clear how HS1BP3 machinery and deserve some special attention:
knockdown correlates with higher autophagy rates;
however, it can be speculated that membranes Phosphoinositides
containing higher concentrations of PA lead to
regions of higher curvature (see below) that In eukaryotes there are seven different PtdIns,
promotes LC3 lipidation and autophagosome derived from the reversible phosphorylation of the
formation. inositol ring of PI at positions 3, 4 and 5. The action of
A lipid-transfer function of ATG2 has recently different lipid kinases and phosphatases mediates
been identified. ATG2 contributes to phagophore the interconversion among these PtdIns, which
expansion by direct phospholipid transfer from ER present low abundance and high turnover in
membranes to the phagophore at contact sites membranes. PtdIns confer unique membrane iden-
[27–29]. Results from these studies show a lipid- tity and serve as membrane-bound signals for
binding specificity for ATG2. Whereas in vitro binding protein effectors at specific sites at a given
ATG2 preferentially transfers PC, PE and PS time. Protein recruitment is mediated through low to
[28], ATG2 from cultured cells copurifies almost moderate interactions with PtdIns-specific binding
exclusively with glycerophospholipids [29]. ATG2 domains (such as FYVE or PX, or the FRRG motif in
presents sequence and structural similarities with the β-propeller of PROPPINs) [36,37] , but typically
VPS13A and VPS13C [42], which have also also involves coincidence detection by binding to a
recently been shown to be lipid transport proteins, membrane-specific protein (such as RAB proteins)
in this case between ER and other organelles [43]. in addition to the specific PtdIns.
Altogether, these results are exciting as identifica- The effect of PtdIns on autophagy is best
tion of lipid transfer proteins may pave the way to characterized for the VPS34/PIK3C3 kinase product
understand the de novo formation of autophagic PtdIns3P. PtdIns3P has a pivotal role in recruitment
membranes and to uncover their lipid composition. of the core autophagy machinery to the phagophore
in order to promote autophagosome nucleation and
Lipids as protein docking platforms to tune cell expansion [46]. Class II PI3K (PIK3C2) can, howev-
processes er, also participate in regulation of autophagosome
biogenesis by contributing to production of PtdIns3P
The presence of sphingolipids (that generally at autophagosome nucleation sites [47]. Levels of
present saturated long acyl chains) contributes to PtdIns3P are additionally regulated by the PtdIns3P
ordered and thick membranes with low flexibility and phosphatases Jumpy (MTMR14) and myotubularin-
fluidity [44]. Together with cholesterol, sphingolipids related protein 3 (MTMR3), which dephosphorylate
tend to form membrane microdomains, known as PtdIns3P, negatively regulating autophagy [48,49].
lipid rafts, with important roles in sorting proteins and Turnover of PtdIns3P can be further regulated
lipids between different membranes. As an example through sequential phosphorylation by additional
ER–mitochondria contact sites are mediated by lipid phosphoinositide kinases. The PtdIns 5-kinase
raft-containing mitochondria-associated membranes FYVE-type zinc finger containing (PIKFYVE) con-
(MAMs) [45] . Phosophoinositides and PE- verts PtdIns3P into PtdIns(3,5)P2, which is involved
conjugated ATG8 family proteins are examples of in autophagosome maturation [50,51] . Tectonin
Fig. 2. Lipids in eukaryotic membranes and its interaction with proteins. (A) Glycerophospholipids, sphingolipids and
sterols are the lipids constituents of eukaryotic membranes. Phospholipids are formed by a core alcohol backbone
(glycerol in the case of glycerophospholipids or sphingosine in the case of sphingomyelin) that is esterified to acyl tails and
to a phosphate group, which is associated to specific alcohols. Diacylglycerol (DAG) is the hydrophobic portion of
glycerophospholipids and contains saturated or cis-unsaturated fatty acyl chains of varying lengths. DAG phosphorylation
yields phosphatidic acid (PA), which in turn can be esterified to distinct alcohol moieties rendering the pool of membrane
glycerophospholipids [38]. Ceramide (Cer) consists of a sphingoid base (sphingosine instead of glycerol) amide-linked to a
very long saturated fatty acid (C16–C32). Cer can be esterified to phosphoryl choline rendering sphingomyelin (SM), but it
can also be conjugated to mono, di- or oligosaccharides based on glucose rendering glycosphingolipids (GSL). Sterols are
non-polar lipids essential for eukaryotes. (B) Phospholipids self-organize in bilayers, with the lipidic tails facing each other
and the polar headgroups in contact with the aqueous phase. Depending on the lipid molecular geometry (cylindrical and
cone- or inverted-cone-shaped), membranes are more or less tightly packed and present planar or curved conformations.
(C) Lipid composition of membranes determines the interaction with peripheral and integral proteins, some of which can
affect the membrane curvature. Specific lipid compositions (e.g., lipid-rafts) can serve as docking platforms for proteins.
Proteins can be attached to membranes by conjugation to lipids, by electrostatic interactions or through lipid-binding
domains, which can recognize specific lipids, in a lock-and-key manner or sense membrane properties like curvature or
packing defects.
domain-containing protein 1 (TECPR1) binds that all become conjugated to PE in the autophagic
PtdIns3P after association with the ATG12-ATG5 membrane [6,63–65].
conjugate (in a complex different and exclusive of These proteins have been thought to function non-
the ATG12–ATG5–ATG16L1 one) to promote autop- redundantly during autophagosome formation and
hagosome–lysosome fusion [52]. At the lysosome, cargo recruitment [66], although more recent data
the inositol polyphosphate-5-phosphatase-E show that ATG8 family proteins are dispensable for
(INPP5E) catalyses the conversion of PtdIns(3,5) autophagosome biogenesis, but essential for proper
P2 to PtdIns3P, and this is found to be important for autophagosome–lysosome fusion [67]. The specific
autophagosome-lysosome fusion [53]. roles of ATG8 family proteins are mostly unknown, but
Other PtdIns have also been implicated in evidence suggests that cargo recognition/recruitment
autophagy. Plasma membrane PtdIns(4,5)P2 con- during selective autophagy is regulated by specific
version to PtdIns(3,4,5)P3 by class I PI3Ks activates ATG8 family proteins [68–70]. LC3B is the Atg8 paralog
mTORC1, leading to inhibition of autophagy [14,54]. best studied to date. PE conjugation of LC3B through
PtdIns(4,5)P 2 , generated by type Iγ phos- the action of the autophagic conjugation machineries
phatidylinositol 4-phosphate 5-kinase isoform 5 (ATG7, ATG10 and ATG7, ATG3 and ATG12–ATG5–
(PIPKγi5), regulates ATG14L function in autophagy ATG16L1) leads to conversion of the cytosolic soluble
initiation [55]. PtdIns5P has been found to act as an form (LC3-I) into the lipid-conjugated form (LC3-II) [71],
alternative to PtdIns3P in autophagy initiation upon a popular marker for the monitoring of the autophagic
glucose starvation [56]. Upon amino acid starvation, flux . Indeed, membrane localization of all ATG8 family
arfaptin2 [a Bin, amphiphysin, and Rvs161/167 proteins depends on their covalent modification by PE
(BAR)-domain containing protein, see below] regu- (in vitro, PS can also serve as an acceptor for ATG8
lates ATG9-mediated delivery of phos- family protein conjugation) [72] and is crucial for the
phatidylinositol 4-kinase class III beta (PI4KIIIβ) to recruitment of protein effectors. The scaffolding role of
the autophagosome initiation site, where PtdIns4P ATG8 family proteins is often mediated by their
production affects autophagosome formation [57]. interaction with a linear motif known as an LC3-
GABA RA P-media ted recruitment of p hos- interacting region (LIR) [73], which is present in cargo
phatidylinositol 4-kinase IIα (PI4KIIα) to autophago- receptors (see below a detailed description of LIR and
somes for PtdIns4P local production is relevant for selective receptors) but also in proteins of the core
autophagosome fusion with lysosomes [58]. More- autophagy machinery in both yeast and mammals
over, PI4KIIα and PIP5Kγ control Rab7 cycling [33,73–81]. Also, PE-bound ATG8 family proteins can
through production of a small pool of PtdIns(4,5)P2 mediate the tethering and hemi-fusion of autophagic
and affect pleckstrin homology domain-containing membranes [82–85]. The N-termini of LC3B and
family M member 1 (PLEKHM1), a regulator of GABARAPL2 present highly basic helices that are
autophagosome–lysosome fusion [59]. After lyso- sufficient and necessary for in vitro liposome mem-
somal degradation is complete, new tubular struc- brane tethering and fusion [84]. Removal of PE-bound
tures emerge from the autolysosomal membrane in Atg8 proteins from the outer membrane of autophago-
a process referred to as autophagic lysosome somes, and the concomitant disassociation of the
reformation (ALR) [60]. Following scission, these autophagic machinery, is a required step before
tubular proto-lysosomes gain acidity and degrada- autophagosome–lysosome fusion in yeast [33] that is
tive capacity to become new functional lysosomes . seemingly conserved in mammals [86]. The ATG8
ALR relies on the conversion of lysosomal PtdIns4P family proteins, thus, constitute another essential
to PtdIns(4,5)P 2 by phosphatidylinositol 4- component of autophagy that needs to be controlled
phosphate 5-kinase type-1 beta (PIP5K1B) [61] . in a spatial and temporal manner for the pathway to
Moreover, mTOR-mediated UVRAG phosphoryla- function.
tion increases formation of lysosomal PtdIns3P,
which is critical for tubule scission during ALR [62].
Membrane curvature
In all, PtdIns modulate the autophagic pathway at all
stages. It is thus a priority to deepen our molecular
Recognition and binding of phospholipids in a lipid
understanding of how they do so in order to advance bilayer is not the only way that membrane processes
our mechanistic insight of autophagy.
can be regulated; the curvature of the membrane is also
an important aspect dictating the recruitment and
ATG8 family proteins efficacy of the autophagy machinery (Fig. 2).
The sole yeast Atg8 protein has diversified into six
human homologs (LC3A, LC3B, LC3C, GABARAP,
A matter of geometry
GABARAPL1 and GABARAPL2), divided into the light
chain 3 (LC3; also known as microtubule-associated Lipids such as PI, PC and PS promote bilayer
proteins MAP1LC3) and the γ-aminobutyric acid formation, while conical shaped lipids such as PE, CL
receptor-associated protein (GABARAP) subfamilies and PA induce membrane bending/membrane
Fig. 3. Specific lipid-binding protein mechanisms in selective autophagy. (A) Autophagic cargo can be recognized/
recruited through different mechanisms. Here we illustrate some modalities: cardiolipin (CL) binds to LC3 proteins through
electrostatic interactions; ATG8 family proteins get recruited to cargo proteins by binding LIR-containing proteins that are
exposed to the cytosol upon organelle damage, as in the case of prohibitin 2 (PHB2), or that are anchored (or recruited) to
the cargo membrane. Some LIR-containing proteins (like BNIP3 and BNIP3L) bind to ATG8 family proteins more efficiently
when they are phosphorylated; autophagic cargo can also be recruited by binding of autophagy receptors (like NDP52 and
OPTN) both to ubiquitinated cargo and ATG8 family proteins (via a LIR region). (B) The autophagy machinery is also
recruited to membranes in various ways. Core autophagy proteins can attach to the membrane through specific lipid-
binding domains (e.g., PROPPINs in WIPI proteins) that recognize specific PtdIns or membrane chemical/physical
properties, by directly interacting with the membrane through an amphipathic helix (e.g., for ATG3 and ATG16L1) or by
conjugation to lipids (as for ATG8 family proteins). (C) Examples of processes described in panels A and B are illustrated
for membrane sequestration of damaged mitochondria.
curvature [87]. Lipids with large polar groups adopt sequestration, while the outer membrane harbors
positive monolayer curvature, whereas conical shaped the interactions with the autophagy machinery and
ones (small polar heads and acyl chains with single cis fuses with the lysosomal membrane. This asym-
double bond in the middle that creates a bend) prefer metry in functions is also seen in regular lipid
negative curvature [40,44]. For example, PtdIns3P is a bilayers, and it is often due to an asymmetric lipid
cone-shaped lipid that, when clustered, can create composition between the two leaflets of the
cytosol-facing buds in the membrane. In autophagy, membrane. Enzymes such as flippases translo-
omegasomes are an example of such structures and cate PE and PS toward the cytosolic leaflet,
serve as platforms for recruitment of the autophagic whereas lipids without sizeable headgroups (i.e.,
machinery [45]. DAG, cholesterol or protonated forms of fatty
acids) can spontaneously translocate [34] . The
resulting asymmetric lipid distribution between the
Asymmetrical distribution two leaflets of the bilayer is another factor inducing
The inner and outer membranes of autophago- membrane curvature [40] . Little is, however,
somes have quite different roles: the inner mem- known about the lipid composition of the two
brane is responsible for cargo interaction and membrane layers of phagophores and
autophagosomes and how this affects autophago- subcellular localization. Because of the large num-
some biogenesis and/or function. ber of lipid-binding domains, as well as lipid
molecules and their variation in headgroup and
acyl tail structure, lipid-mediated protein targeting
Curvature generated by protein interaction provides strict control and versatility for interactions.
Interaction between membrane and proteins can Many classical lipid-binding protein domain struc-
also affect the curvature of the former. Membrane- tures have been identified to date, including C1, C2,
adsorbed proteins and wedge-shaped integral PH, FERM, PDZ, GRAM, PX, FYVE and tubby
membrane proteins can induce deformations that domains [95]. Some lipid-binding domains can, in
lead to membrane bending. As an example, sorting addition to interaction with discrete lipid headgroups,
nexin 18 (SNX18; a protein that contains PX-BAR recognize the curvature of lipid membranes, includ-
domains, see below) promotes autophagy by ing BAR domains and amphipathic lipid packing
inducing the formation of tubular structures from sensor (ALPS) motifs. BAR domains are the best
recycling endosomes that serve as membrane input example of such domains; they sense membrane
for autophagosome expansion [88]. Sufficient local curvature by insertion of an amphipathic α-helix into
concentration of a protein on one side of the membrane defects and also by electrostatic interac-
membrane is thought to generate curvature by tions with negative charges in the membrane [96,97].
”crowding effect” [89]. Also, certain proteins (de- ALPS motifs are intrinsically unfolded sequences
pending on their shape or oligomeric state) can that form amphipathic helices at the surface of highly
stabilize membrane geometries by associating with curved membranes [96,97].
lipid headgroups and forming a membrane scaffold. There are many examples of lipid binding and
As an example, yeast Atg12–Atg5 binds to Atg16 curvature sensing proteins involved in autophagy
(that itself forms dimers) forming a multimeric [98]. Several components of the ULK complex
complex that can act as an scaffold and stabilize present lipid-binding domains, which are likely to
membrane structures [90]. Mammalian ATG16L1 facilitate membrane recruitment. In vitro yeast Atg1
seems to work also as a dimer [91]. Recently, three shows high affinity to highly curved liposomes (20–
30 nm) [99]. The C-terminus of ULK1 (and of yeast
independent lipid-binding domains have been iden-
ortholog Atg1) has an early autophagy targeting/
tified in ATG16L1 [92,93]. ATG16L1 could thus be
tethering (EAT) domain [100] that seems to sense
considered a coincidence detector that binds both
membrane curvature, as it binds to liposomes in a
lipids and protein effectors (e.g., WIPI2) in order to
geometry-dependent manner [101] . The C-terminal
ensure a proper membrane localization.
region of the PIK3C3 complex I member ATG14L1
contains a Barkor/Atg14 autophagosome targeting
Membrane electrostatics
sequence (BATS) domain [102] that might facilitate
binding to highly curved structures and/or be
Charge of the polar head (neutral or negative)
differs among phospholipids. PS, PA, PI, PtdIns and important for the stabilization of the phagophore
curvature. Another PIK3C3 complex I member,
CL all contain negatively charged headgroups,
Beclin 1, also presents a β-α-repeat autophagy
which confers anionic charge to the harboring
membrane [34] . The presence of conical shape domain (BARAD) for membrane association [103].
ATG8 family protein lipidation is also highly curva-
lipids (e.g., PA) in flat membranes causes what is
ture sensitive [97]. ATG3 facilitates lipidation prefer-
known as “lipid packing defects,” which results in
entially on membranes exhibiting local lipid packing
hydrophobic acyl chains exposure to the aqueous
defects, thanks to the presence of an amphipathic
environment if lipids are aligned in a two-dimensional
alpha helix in its N-terminus [104]. Also, ATG12–
plane. In autophagy, the N-terminus of ATG13
ATG5–ATG16L1-mediated conjugation of LC3 or
presents a cluster of positive amino acids that
GABARAP to PE has been shown to occur more
interacts with acidic phospholipids and provides
efficiently on liposomes with high curvature (25–65
membrane binding important for the translocation
nm) compared to larger liposomes (~ 400 nm) with
of ATG13 to phagophore during nucleation [94].
Lipid packing defects can be also achieved in small relatively low curvature [92], reinforcing the idea of
membrane elongation through lipidation of ATG8
vesicles and tubules as result of high membrane
family proteins occurring at the highly curved ends of
curvature [34], similar to what is seen at the rim of the
the phagophore.
phagophore.
Lipid-binding domains Selective autophagy

Several proteins involved in signaling and traffick- Selective autophagy is a general term used to
ing contain specific lipid-binding domains that describe a range of processes that enrichen and
recognize their target lipid and allow a specific degrade specific cargo via the autophagy machinery
rather than the seemingly “random” or “bulk” uptake as neighbor of BRCA1 Gene (NBR1) that was shown
attributed to starvation-induced autophagy. This to follow a similar principle of dual-binding to
cargo can range from specific proteins, such as ubiquitinated cargos via a ubiquitin binding domain
ferritin (ferritinophagy) [105], poly-carbohydrates and to LC3 via a LIR [121].
such as glycogen (glycophagy) [106] or multi- It is important to note that the LIR motif (repre-
protein aggregates (aggrephagy) [107] and up to sented by amino acid properties as [-][-][-]ΘxxГ) has
entire organelles such as mitochondria (mitophagy) since become well defined and identified in a
[108], peroxisomes (pexophagy) [109], lipid droplets constantly growing number of proteins [76]. While
(lipophagy) [110] or invading bacteria (xenophagy) originally defined in cytosolic receptor proteins such
[111,112]. The general trafficking concept in each of as p62, NBR1 or calcium-binding and coiled-coil
these contexts is similar; the specific cargo is taken domain-containing protein 2 (CALCOCO2), it has
up into a double-membraned autophagosome and also been identified in cargo-specific transmem-
trafficked to the lysosome for degradation. Many of brane proteins, such as BCL2/Adenovirus E1B 19
the earlier discussed points surrounding lipids and kDa protein-interacting protein 3 (BNIP3), BNIP3-
membrane events in autophagy are broadly appli- like (BNIP3L), FUN domain-containing protein 1
cable to selective autophagy pathways also. Indeed, (FUNDC1) and FAM134B. Thus, autophagy recep-
two of the key initiating kinases, ULK1 and VPS34, tors can both facilitate cargo degradation by medi-
also seem to be required in many forms of selective ating interaction between a cargo protein (often
autophagy, including mitophagy [113,114], lipo- ubiquitinated) and LC3 in the autophagosomal
phagy [110], pexophagy [115,116], aggrephagy membrane and by direct cargo recruitment of LC3
[117] and xenophagy [118]. when directly embedded/linked to the autophagy
The clearest difference that is currently observed target (often by intrinsic transmembrane domains as
between these selective forms of autophagy ap- is seen in mitophagy receptors BNIP3/BNIP3L or
pears to be in the labeling and recognition stage of ER-phagy receptor FAM134B) (Fig. 3).
cargo that is to be degraded, with many different While many LIR motifs contain three acidic
proteins and pathways identified. This situation can residues at the start, not all are found to contain
be further complicated by the fact that different this and, in approximately 25% of cases, contain a
stimuli can potentially trigger degradation of the phosphorylatable residue instead [73]. This, howev-
same cargo (e.g., mitochondria) by different er, leads them susceptible to an interesting form of
pathways. regulation first revealed with the adaptor protein
optineurin (OPTN). OPTN contains a serine residue
Lipid recruitment of autophagy receptors within the LIR sequence (EDSFVEI) that when
phosphorylated introduces a negative charge akin
For selective degradation of a cargo to occur, to an acidic residue that can enhance binding to the
binding and sequestration of that cargo into the basic patch in LC3 and is therefore sufficient to act
autophagosome must first take place. To date as an on/off switch for LC3 binding [122]. In this
extensive focus has been placed upon so-called instance, phosphorylation of OPTN was demonstrat-
autophagy receptor proteins that can bridge the gap ed to be mediated by the serine/threonine-protein
and link cargo directly to the inner autophagosomal kinase TANK-binding kinase 1 (TBK1) in response to
membrane; much of our current knowledge of cellular Salmonella infection and formed a critical
selective autophagy has been garnered from these part of the cellular response, as preventing this
protein–protein interactions. phosphorylation reduced the efficiency of LC3
The integral presence of ATG8 family members on targeting to invading Salmonella [123]. The concept
the inner autophagic membrane provides a conve- of LIR phosphorylation has also been observed with
nient mechanism and anchor point for linking the mitophagy receptor BNIP3L that contains no N-
proteins to the autophagosome for degradation. terminal acidic residues in the LIR motif
The ability of certain proteins to act as intermediates (NSSWVEL). Phosphorylation of the two serine
or so-called autophagy receptor proteins in the residues enhances LC3B binding affinity up to 100-
binding of a ubiquitinated cargo to LC3 in the fold [124]. Other LIRs that contain N-terminal
membrane was first demonstrated with the protein serines, such as those seen in FUNDC1 and
sequestosome-1 (SQSTM1; here referred to as p62) BNIP3, have also been shown to be responsive to
[107]. This pioneering work lead to identification of a phosphorylation [114,125,126]. From this initially
short acidic LC3 interacting region (LIR) in p62 that defined LIR, several other subtypes have emerged,
binds to a basic region in LC3 (R10/R11/K51) while such as the extended LIR as seen in FYVE and
simultaneously binding ubiquitin via a separate coiled-coil domain-containing protein 1 (FYCO1)
ubiquitin binding domain, leading to targeting of [127], atypical LIR (CLIR) in NDP52 [128] or the
ubiquitinated aggregated proteins for inclusion into GABARAP interaction motif (GIM) that confers
autophagosomes [119,120]. This set the ground selectivity to the GABARAP family binding and is
work for identification of other receptor proteins such seen in PLEKHM1 [129]. The identification of LIRS,
extended LIRS and GIMS has proved to be a key codon that causes loss of the C-terminal FYVE and
turning point in the field of autophagy research and WD-40 domains in mice leads to several neurode-
contributed significantly to the identification of many velopmental abnormalities, but the role of the FYVE
novel LIR containing and autophagy linked proteins. domain is not currently clear [138,139].
The development of web resources such as iLIR has These are just three examples of proteins con-
also made it easy for researchers to check proteins taining both a LIR/GIM and lipid-binding domains,
of interest for possible LIRs and introduce simple but given the growing prevalence of LIR motifs and
point mutations to test LC3/GABARAP binding [130]. the number of defined lipid binding domains, it will
It is important to remember that during autophagy not be surprising if there are more lipid binding
many different membrane compartments are in- proteins waiting to be linked in a similar manner.
volved, each with their own lipid composition that is FYCO1 and PLEKHM1 both associate with the outer
also subject to its own form of regulation such as membrane of the autophagosome and mediate
PtdIns and their phosphorylation/de- interactions with its environment, functionally assist-
phosphorylation. Of particular interest in the context ing in trafficking and lysosomal fusion. It awaits to be
of this review is the identification of receptor proteins seen if this is a general trend that LIR containing lipid
that also contain the capacity to interact with lipid binding proteins are more frequently associated with
membranes. outer membrane ATG8s.
The LIR containing protein FYCO1 also contains a
FYVE domain, a zinc finger domain that can bind ER-phagy and LIRs
specifically to the lipid PtdIns3P in co-ordination with
two Zn 2+ ions [131,132]. During autophagy, FYCO1 The endoplasmic reticulum (ER) is a large cell-
can act as an adaptor protein; rather than being spanning organelle composed of a series of inter-
recruited inside the autophagosome, it binds to LC3 connected tubules and sheets that are the site of
on the outer membrane of the autophagosome. multiple cellular processes, including lipid and
FYCO1–LC3 binding promotes re-distribution of protein synthesis, quality control of newly formed
autophagosomes to the positive end of microtubules proteins and communication between organelles.
as FYCO1 also binds to kinesins [133]. Interestingly, ER tubules tend to be highly mobile, forming and
binding of FYCO1 to LC3 allows PtdIns3P interac- retracting along cytoskeletal components with rela-
tion of its FYVE domain, which is usually folded and tively high membrane curvature. This high curvature
occluded from interaction with PtdIns3P, suggesting is largely generated and stabilized by the presence
a specific role of this domain when recruited to LC3 of reticulon proteins that can themselves induce
containing membranes [133]. It may be interesting to membrane curvature through wedge-shaped hydro-
examine whether the dual binding of LC3 and phobic domains [140,141]. ER sheets by contrast
PtdIns3P plays an important role in the specific are less mobile than tubules but can still enlarge in
distribution of FYCO1 to the outer membrane during response to specific stimuli and generally have low
autophagosome formation. levels of lipid curvature [142]. In recent years, the
The protein PLEKHM1 also binds to the outer importance of ER-phagy in maintenance of cellular
membrane of autophagosomes via interactions with homeostasis has begun to be uncovered with
GABARAP via a GIM. PLEKHM1 regulates interac- multiple ER-phagy receptor proteins identified;
tions between the autophagosome and the homo- these are localized to different sub-structures of the
typic fusion and protein sorting (HOPS) complex; ER and play different roles in the overall health of this
this is critical for facilitating fusion of autophago- organelle and the cell itself. Indeed, genetic defi-
somes with lysosomes [134]. The RUN domain of ciency in some ER-phagy receptors has been shown
PLEKHM1 mediates its direct interaction with the to lead to the degradation of sensory neurons or
HOPS complex; however, PLEKHM1 also contains proteostatic defects of the pancreas [143,144].
two PH domains and a C1 domain that can both The first identified ER-phagy receptor protein was
potentially bind to lipids. Hijacked recruitment of FAM134B, an ER resident protein found within sheet
PLEKHM1 via PH domain 2 and the C1 domain by regions [143]. FAM134B contains a reticulon homol-
Salmonella has been demonstrated to occur as part ogy domain that, like reticulon proteins, inserts a
of Salmonella proliferation, but a role for these wedge-shaped hydrophobic structure into the mem-
domains during normal cellular homeostasis has not brane inducing membrane curvature [141].
yet been identified [135]. Furthermore, the protein FAM134B is found primarily at ER sheet edges
autophagy-linked FYVE protein (ALFY) contains and can bend the ER membrane structure, an
both a FYVE domain capable of binding PtdIns3P important step in promoting ER fragmentation via
and a LIR with preference for GABARAP binding atlastin 2 (ATL2; a dynamin like GTPase) [145].
[68,136]. ALFY appears to act as a scaffolding Following fragmentation of the ER, FAM134B
protein required for selective autophagy, but non- mediates uptake of these ER sheet fragments into
essential for starvation induced autophagy [137]. the autophagosome by a LIR domain interaction with
Loss of ALFY or introduction of a premature stop LC3 [143]. Modulation of the lipid bilayer by the
Table 1. Lipid composition of subcellular fractions of rat liver (data from Ref. [175])
Lipid Mitochondria ER Lysosomes Golgi Plasma membrane
Phospholipids (mg/mg/protein) 0.175 0.374 0.156 0.825 0.672
Sterols (mg/mg protein) 0.003 0.014 0.038 0.038 0.128
PC (%) 44 60 48 51 40
PE (%) 34 23 17 21 24
PI (%) 5 10 6 12 8
PS (%) 1 2 3 6 9
Cardiolipin (%) 14 1 1 1 1
PA (%) b1 1 1 b1 1
Sphingomyelin (%) 1 3 24 8 17
reticulon homology domain is therefore a key step in facilitate fragmentation of the ER network and
this form of ER-phagy that is essential to allow efficient uptake into the autophagosome. The
fragmentation and uptake into the autophagosome. mechanisms underlying such changes are, howev-
Sec62 is another ER sheet localized protein that is er, largely unknown.
also shown to induce degradation of sheet regions of
the ER following an ER stress response (in this case Mitophagy and LIRs
induced by cyclopiazonic acid) [146].
The long isoform of reticulon 3 (RTN3L), like other Mitochondria are double-membrane enclosed
reticulon family members, is an ER tubule protein, organelles that regulate multiple cellular processes,
but is the only reticulon able to interact with ATG8 although arguably, they are most notable for their
family proteins via any one of six LIR motifs. Self- role in generating ATP via oxidative phosphoryla-
oligomerization of RTN3L on tubules is required to tion [151]. Electrons harnessed for oxidative phos-
induce ER fragmentation and degradation of these phorylation can, however, sometimes be lost and
tubular fragments occurs by LIR binding of RTN3L to lead to generation of reactive oxygen species
both LC3 and GABARAP proteins [147]. Cell cycle (ROS). In addition, mitochondria contain cyto-
progression gene 1 (CCPG1) by contrast is another chrome C that upon mitochondrial release can
ER resident protein whose expression is induced by induce a form of programmed cell death [152,153].
the unfolded protein response (UPR). CCPG1 Damaged mitochondria therefore risk significant
appears to accumulate in regions of the ER with harm to the cell via release of ROS and/or
insoluble proteins and acts as a link between the cytochrome C, and their rapid clearance by mito-
UPR and ER-phagy; data from CCPG1 −/− mice phagy is important for cell survival.
suggest that this is critical for clearance of insoluble Mitophagy has received considerable interest due
proteins in pancreatic tissue [144]. to commonly observed mitochondrial dysfunction in
Most recently, another atlastin family member, association with multiple neurobiological disorders
ATL3, has also been implicated in selective degra- such as Alzheimer’s and Parkinson’s disease. While
dation of ER tubules by directly interacting with largely a non-hereditary disease, the identification of
GABARAP family members via two distinct GIM two major Parkinson’s causing genes, PINK1 and
motifs. ATL3 appears to be important for tubular ER- PARKIN, playing a role in mitophagy has caused
phagy in tissues that lack RTN3L expression and act huge amounts of interest and research into this
distinct from one another; loss of ATL3 could be subject [154,155]. It is not in our interest to go into too
compensated by expression of RTN3L [148]. Impor- much depth regarding the PINK1/PARKIN pathway
tantly, mutation of ATL3 (Y192C and P338R) is seen in the context of this review; however, it is worth
in patients with hereditary sensory and autonomic noting that due to the coordinated research between
neuropathy type I (HSAN I) [149,150], mutation of many laboratories, it has been elegantly studied in
these sites demonstrates reduced interaction with great depth and huge strides forward have been
GABARAP in vitro further demonstrating the impor- made in determining spatially and temporally the
tance of efficient ER-phagy for peripheral neuronal sequence of events that occur following mitochon-
health. drial membrane depolarization. In brief, loss of the
All ER-phagy discovered to date therefore works mitochondrial gradient leads to the stabilization of
off the principle of receptor proteins embedded in the protein kinase PINK1 in the outer mitochondrial
the ER membrane and clearance via LIR mediated membrane, where it phosphorylates ubiquitin and
interaction with the autophagy machinery. Of most recruits the E3 ligase PARKIN [156,157]. Ubiquitina-
interest in the context of this review is the ER tion of multiple outer mitochondrial membrane
membrane changes that appear to be needed to proteins by PARKIN leads to recruitment of some
of the cytosolic ubiquitin-binding autophagy recep- ent mitophagy receptors under various metabolic
tors, such as OPTN and NDP52 facilitating uptake of and pathophysiological conditions remains some-
the mitochondria into the autophagosome and what elusive. At each of their core functions,
degradation [158–160]. In addition to PINK1, the however, is a specific LIR motif and ATG8 family
inner-mitochondrial proteins 4-nitrophenylphospha- interaction that allows the protein to act as a receptor
tase domain and nonneuronal SNAP25-like protein for uptake into the autophagosome.
homolog (NIPSNAP) 1 and 2 were recently found to
accumulate on the surface of depolarized mitochon- Mitophagy and cardiolipin
dria, where they function as eat me signals for
recruitment of autophagy receptors [161]. Although While most research has focused on the involve-
recent in vivo data from mice [162] and Drosophila ment of ubiquitin or receptor proteins, it may be naïve
[163] dispute the relevance of PARKIN for basal to assume that other characteristics of mitochondria
mitophagy, zebrafish larvae lacking a functional such as lipids have no role to play in their regulation.
Nipsnap1 displayed a parkinsonian phenotype [161]. Like all cellular membranes, mitochondria have
A PINK/PARKIN-independent form of mitophagy their own unique lipid fingerprint that can determine
exists that is not induced directly by or responsive to membrane identity and dictate unique interactions.
damage, but is rather a programmed form based In contrast to other organelles, mitochondria tend to
upon the metabolic requirements of the cell or contain relatively low levels of proteins or sterols
cellular fate. This was first demonstrated in red relative to their phospholipid concentration (Table 1).
blood cells, which remove their mitochondria in a In addition, they have lower PI and PS concentra-
programmed manner as they mature [164]. The tions compared to other cell organelles [175]. By
outer mitochondrial transmembrane protein and contrast, mitochondria boast one specific lipid
autophagy receptor BNIP3L (also called NIX) was species not present in other membranes. Cardiolipin
found to regulate the removal of mitochondria from (CL) is a phospholipid that makes up approximately
erythrocytes [165,166]. It has since be found that 14% of mitochondrial phospholipid abundance [176].
BNIP3L contains an N-terminal LIR motif that is Another unique aspect of mitochondria is their
required for ATG8 family recruitment [167]. Interest- double-membrane structure, containing both an
ingly, the LIR of BNIP3L does not contain any acidic inner mitochondrial membrane (IMM) and outer
residues, but does contain two serines that upon mitochondrial membrane (OMM) each with their
phosphorylation enhance LC3B binding by 100-fold, own distribution and enrichment of lipids. CL
although a kinase that mediates this phosphorylation displays extraordinary asymmetry, with estimates
is yet to be determined [124]. BNIP3 is another outer of ~ 97% of CL found on the IMM [177]. This is largely
mitochondrial transmembrane receptor that has its a consequence of its synthesis on the inner leaflet of
expression strongly controlled and often upregulated the IMM from phosphatidylglycerol (PG) by CL
in response to stress such as hypoxia [168]. BNIP3 synthase [178].
can also bind to LC3 via a LIR motif that regulates Phospholipids have a general structure of two
mitochondrial turnover [169,170]. Similar to other
hydrophobic acyl chains joined to a glycerol back-
autophagy receptors, it also contains a serine
bone that links the fatty acids to a polar phosphate
residue that enhances binding to LC3 in response molecule and lipid-specific headgroup (Fig. 2). CL is
to phosphorylation [126].
unique in that it is composed of essentially two units
Several other distinct mechanisms of mitophagy
each containing 2 × acyl chains connected to
involving LIR interactions have been determined.
glycerol and a phosphate head; these phosphate
These include the inner mitochondrial membrane
headgroups are linked by a glycerol bridge [179]. CL
protein Prohibitin 2 (PHB2) that is accessible to LC3
is therefore both strongly negative charged and
binding following permeabilization of the outer
highly hydrophobic. crdΔ yeast (lacking CL syn-
mitochondrial membrane [171]. Furthermore, a pool
thase) exhibit lower oxidative phosphorylation rates,
of the protein activating molecule in BECN1-
mitochondrial protein import and mtDNA instability
regulated autophagy protein 1 (AMBRA1) is also
highlighting the critical role of CL in normal mito-
shown to localize to the outer mitochondrial mem- chondrial function [180].
brane and is able to recruit LC3 via a LIR for
mitochondrial turnover [172,173]. FKBP8 is another While CL is primarily found in the matrix fold of the
outer mitochondrial membrane anchored protein that IMM, it has been found to become exposed on the
can recruit LC3A via a LIR motif in response to OMM in response to various stress stimuli [181,182].
carbonyl cyanide m-chlorophenyl hydrazone Exposure to the cytoplasmic environment acts as a
(CCCP) treatment [174]. stress signal akin to how phosphatidylserine (PS)
Thus, a large number of mitophagy receptors have exposure on the outer cell membrane can trigger
been implicated in the turnover of mitochondria, cellular uptake by macrophages [183]. The move-
where some are cytosolic while others are integral ment of CL requires sequential movement from
mitochondria proteins. The importance of the differ- matrix facing, to the intermembrane space and then
subsequently between the IMM and OMM for irradiation; this and other post-translational modifi-
exposure to the cytoplasmic environment. cations may play important roles under depolarized
Phospholipid scramblases (PLSCR family) are conditions [189].
enzymes involved in the trans-bilayer movement of Anionic CL that is presented on the OMM has been
phospholipids in a calcium-dependent manner, shown to interact with LC3 proteins via electrostatic
which was first exemplified on PS by PLSCR1 interactions and is required for recruiting autophago-
[184]. Another PLS family member, PLSCR3, is somes to depolarized mitochondria. LC3 family
localized to mitochondria and is shown to regulate members contain a positively charged α1 helix not
both CL synthesis and movement to the OMM observed in GABARAP family members [190].
[181,185]. In response to UV irradiation, CL is Deletion of the α1 + α2 helices or mutation of
redistributed to the OMM (approx. 2-fold higher) R10L/R11L in LC3B prevents recruitment to mito-
and this recruits BH3-interacting domain death chondria after rotenone exposure [182]. As predict-
agonist (BID) to stimulate cytochrome C release ed, GABARAP proteins lack basic residues at this
[181,186]. Blocking PLSCR3 by mutating the calci- region and show no CL-mediated mitochondrial
um binding domain [181] or knockdown by siRNA recruitment [182]. While the interaction is electro-
[182,185] prevents this redistribution of CL to the static, charge alone does not dictate binding.
OMM. The availability of CL on the outer mitochon- Incubation of LC3B with another di-anionic lipid
drial membrane is therefore a key signaling move- (PtdIns4P), or even tri-anionic (PtdIns(4,5)P2),
ment that allows accession and interaction with showed no binding affinity, suggesting that the
cytoplasmic proteins. More recently work has shown LC3–CL interaction is still specific [191].
that PLSCR3 is localized and anchored in the IMM The phenomenon of OMM CL exposure leading
with its calcium-responsive domain facing the to protein recruitment is not only confined to LC3
intermembrane space and is suggested to “flip” CL binding. More recently, the PH domain of p210
from matrix facing to intermembrane space facing on BCR-ABL, which has previously been shown to
the IMM [187]. This work also suggested that protons bind PtdIns(4,5)P2 [192,193], was found to bind
(H +) that would be expected to be present in the strongly to small unilamellar vesicles containing CL
intermembrane space with an intact mitochondrial through the same basic residues that mediate
gradient (pH 5.8) can also stimulate PLSCR3 activity binding to PtdIns species. Upon treatment with
to the same extent as Ca 2+ , suggesting that CCCP, mitochondria were able to recruit p210
PLSCR3 is active under normal respiring mitochon- BCR-ABL, but not a PtdIns/CL binding-deficient
drial conditions [187]. The protein mitochondrial mutant (R726A) [194]. This opens an exciting new
nucleoside diphosphate kinase (NDPK-D/NME) is possibility for research. It is estimated that roughly
localized to the IMM [188] and has also been shown 10% of PH domain proteins can bind to PtdIns, with
to possess CL transfer activity, important for OMM preference for di-phosphorylated PtdIns [195].
exposure of CL [177]. The necessity of both These data suggest that some of these PH domains
PLSCR3 and NDPK-D for CL OMM exposure can also potentially bind directly to lipids such as
suggests that these proteins may function together CL, which may lead to identification of previously
in the same CL transfer pathway, with PLSCR3 unknown mitochondrial regulators. Interestingly,
mediating the first flip step and NDPK-D transferring other lipid-binding domains such as the PX domain
CL from IMM to OMM (inner leaflet). How CL of HS1BP3 have also been seen to bind to CL
ultimately flips to the cytosolic side of the OMM is through lipid-overlay strips, although it is unclear if
still uncertain. this is also observed in cells and whether HS1BP3
Mitochondrial damaging agents such as CCCP regulates mitophagy [41]. Other PX domain pro-
(H + ionophore) or Rotenone (complex I inhibitor) that teins such as SNX18 have in the past demonstrated
cause mitochondrial depolarization also trigger the preference for binding to PtdIns(4,5)P2 similar to PH
redistribution of CL, resulting in an approx. 2- to 10- domain proteins; it will be interesting to examine
fold increase in OMM CL [177,182]. Precisely why whether these can also potentially bind and interact
mitochondrial depolarization can stimulate CL trans- with CL [196].
fer to the OMM is currently unclear, considering H + Many studies to date examining lipid-binding
ions positively regulate PLSCR3 activity and this domains have taken advantage of phospholipid
would be lost under such circumstances [187]. overlay strips to probe for binding ability; however,
Mitochondria do, however, hold significant matrix this may have caused problems in two manners.
localized calcium stores (normally accumulated by First, many of the commercially available and
the large electrochemical gradient), and it is possible utilized lipid strips contain multiple PtdIns species
that H + ions are replaced by Ca 2+ in such alongside PA/PE/PS and PC, but generally not CL,
circumstances. It has been shown, however, that potentially overlooking the possibility of CL binding.
PLSCR3 can also be stimulated by phosphorylation Second, the overlay strip poorly replicates the true
and has been shown to be a substrate and activated binding surface for these domains and experiments
by protein kinase c delta (PRKCD) in response to UV with small unilamellar vesicles have shown better
results, as has been the case with p210 BCR-ABL tration into autophagosomes [205,206]. ALFY is a
[193,194,197]. Given the growing importance of CL large scaffolding protein that binds to PtdIns3P
in mitochondrial regulation, it will be interesting to through a C-terminal FYVE domain [136]. ALFY
examine whether any other lipid binding proteins binding to GABARAP subfamily proteins enhances
have been overlooked that could provide novel and its specificity toward autophagic membranes [68].
fascinating insights into mitochondrial turnover. ALFY has been described to be dispensable for
With regard to other lipids important for mitochon- starvation-induced autophagy, but required for
drial regulation, it has been suggested that small aggrephagy [137].
amounts of PtdIns(4,5)P2 are present on the outer Such a mechanism in which binding to both PtdIns
mitochondrial membrane where it is important for and ATG8 family proteins facilitates protein aggregate
mitochondrial fusion/fission regulation. Caution clearance is also used in other organisms. In yeast,
should, however, now be taken when interpreting phagophores nucleate from a single phagophore
these data, as this was determined using the PH assembly site (PAS; which is localized close to the
domain of PLC1-delta [198,199], a classic binder of vacuole), sequester the cargo and deliver it to the
PtdIns(4,5)P2 that potentially also could bind to CL, vacuole for degradation [207]. The Cvt pathway is a
which was not tested [200]. Retargeting SKIP1 biosynthetic pathway considered the paradigm of
(INPP5K), an inositol-5 phosphatase, to the mito- selective autophagy in Saccharomyces cerevisiae. It
chondrial membrane, however, also led to mito- exploits the autophagy machinery to deliver hydro-
chondrial fission, suggesting that the presence of lases, such as α-mannosidase (Ams1), aminopepti-
PtdIns(4,5)P2 may be true [199]. It will be intriguing dase 1 (Ape1) and aspartyl aminopeptidase (Ape4) to
to see more data on the importance of PtdIns the vacuole [208–211]. prApe1, the zymogen form of
species on mitochondrial membranes for their the Ape1, is the main cargo of the Cvt pathway. prApe1
regulation. is synthesized in the cytosol, where it oligomerizes into
Mitochondria are a startling example of the dodecamers that further aggregate into bigger struc-
complexity of selective autophagy pathways, dem- tures, sequestered into a Cvt vesicle and delivered to
onstrating several distinct mechanisms for clearance the vacuole, where it is activated by removal of the N-
of the same organelle. These include utilization of terminal propeptide [212]. Cvt can thus be seen as an
ubiquitin binding cargo receptors in PINK1/PARKIN- example of aggrephagy. Atg19 is the cargo receptor
dependent mitophagy [158], transmembrane recep- that selectively binds the propeptide region of prApe1
tors BNIP3/BNIP3L in hypoxia/programmed mito- forming the Cvt complex. This Cvt complex is then
phagy [165,170], OMM/IMM LIR receptors FKBP8, recruited to the PAS via an interaction with Atg11.
AMBRA1, PHB2 [171,173,174] and CL OMM expo- There, Atg19 interaction with Atg8 mediates the
sure during membrane depolarization [182], all engulfment of the Cvt complex into a Cvt vesicle. The
representing unique pathways that ultimately aim proper localization of Atg8 is mediated by PtdIns and
to remove the mitochondria by autophagy (Fig. 3). Atg21 can bind to PtdIns3P and PtdIns(3,5)P2 and
The relative importance of each of these pathways interacts with Atg8 and Atg16 [213,214]. Thus, the
on a whole organism level is unclear, but it seems binding of Atg21 to PtdIns3P on the phagophore
certain that they are very much context and cell type membrane ensures recruitment of Atg12–Atg5–Atg16
dependent. and efficient lipidation of Atg8 on these structures.
Peroxisomes are dynamic organelles important for
Lipids and lipid-binding proteins in other types the metabolism of lipids and reactive oxygen species.
of selective autophagy Peroxisome homeostasis is achieved by a controlled
balance between peroxisome biogenesis and
Unfortunately, detailed information about the role autophagy-mediated selective degradation or pexo-
of lipids and associated proteins in other types of phagy, when such balance is lost it leads to multi-
selective degradation by autophagy is scarce. There systemic diseases [215]. NBR1 is involved in clustering
are, however, discrete pieces of information for and degradation of peroxisomes, and the binding of the
specific processes that we have put together in this autophagic receptor to the organelles is mediated by a
section. membrane-interacting amphipathic α-helix preceding
Aggrephagy refers to the autophagic clearance of the ubiquitin-associated domain, the JUBA or J domain
aggregation-prone proteins [107] such as huntingtin [216], first described as essential for NBR1 localization
[201], α-synuclein [202] and amyloid-β [203] that to late endosomes [217].
when accumulated lead to several neurodegenera- Lipids and associated proteins have important roles
tive diseases [204]. Ubiquitination of misfolded in regulating selective types of autophagy; however,
proteins is a key regulator in recognition and further investigations are needed to put together the
autophagy-mediated degradation of protein aggre- pieces of information we have and to achieve a general
gates. Receptors p62, NBR1 and TOLLIP are overview of how this regulation is performed at different
ubiquitin-binding and LIR-containing proteins that stages of autophagy and among the different types of
mediate protein aggregate recognition and seques- selective autophagy.
Neutral lipids and lipophagy autophagic membrane, the mechanisms linking

cargo to the autophagy membrane or the determi-
Lipid droplets (LDs) are storage organelles for nants controlling the shape and size of the
neutral lipids, formed by a triacylglycerol (TAG) and phagophore remain unanswered and need to be
steryl-ester (SE) core surrounded by a phospholipid investigated.
monolayer [218]. In lipophagy, LDs constitute the
cargo that is selectively targeted for lysosomal
degradation [110]. Breakdown of LDs leads to
production of fatty acids and sterols, which are
utilized for energy homeostasis and membrane Acknowledgments
biogenesis. Mobilization of neutral lipids from LDs
can contribute to the formation of autophagic This work was supported by the Research Council
membranes and might be mediated by ATG2 of Norway (project number 221831) and through its
(recently identified as a lipid-transfer protein, see Centres of Excellence funding scheme (project
above), which seems to regulate LDs in an number 262652), as well as the Norwegian Cancer
autophagy-independent manner [219,220]. This Society (project number 171318). The research
could happen through a kiss-and-run process, in leading to this article has also received funding
which the LDs would transfer lipids to the outside from the European Union Seventh Framework
membrane of the phagophore (possibly contributing Programme (FP7-PEOPLE-2013-COFUND) under
to membrane curvature through asymmetric lipid grant agreement no. 609020 Scientia Fellows.
distribution or by donating curvature-inducing lipids
as DAG) [221] or by reverse flux of lipids from the Received 12 April 2019;
LDs to the ER and then to the forming autophago- Received in revised form 29 May 2019;
some [222,223]. Autophagy seems to have a role in Available online xxxx
modulating lipid stores in the cell by coupling
consumption to biogenesis in order to avoid lipotoxi- Keywords:
city, a condition that occurs when fatty acid storage membrane;
in lipid droplets is impaired or the storage capacity is lipid-binding domain;
overwhelmed and can result in disease [224]. lipid–protein interaction;
mitophagy;
lipid regulation
Discussion and/or Perspectives
To capture widely relevant insight into the
molecular mechanisms of autophagy, it is essential
to get to know the specific lipids that constitute
autophagic membrane(s) and to better understand Abbreviations used:
their role in controlling the multiple membrane ALFY, autophagy-linked FYVE protein; AMBRA1, acti-
modeling events occurring in this degradative vating molecule in BECN1-regulated autophagy protein 1;
pathway. In this review, we have described multiple ATG, AuTophaGy-related; BAR, Bin, amphiphysin, and
roles by which lipids actively participate in regulat- Rvs161/167; BNIP3, BCL2/Adenovirus E1B 19 kDa
ing protein activity, trafficking and localization. protein-interacting protein 3; BNIP3L, BCL2/Adenovirus
Unfortunately, specific information about the role E1B 19 kDa protein-interacting protein 3-like;
of lipids in autophagy in general (and in selective CALCOCO2, calcium-binding and coiled-coil domain-
autophagy in particular) is very limited, and this containing protein 2; CCCP, carbonyl cyanide m-
serves to highlight the difficulty in studying such chlorophenyl hydrazone; Cer, ceramide; CL, cardiolipin;
systems. Although the mechanisms by which the ER, endoplasmic reticulum; FUNDC1, FUN domain-
core machinery of autophagy interacts with mem- containing protein 1; FYCO1, FYVE and coiled-coil
branes should apply for both bulk and selective domain-containing protein 1; GABARAP, gamma amino-
autophagy, experimental evidence is needed to butyric acid receptor-associated protein; GIM, GABARAP
know whether that is the case. But there seems to interaction motif; GLS, glycosphingolipids; HS1BP3,
be hope; over the time, we have spent writing this HCLS1 binding protein 3; HOPS, homotypic fusion and
review many new studies (eight papers since the protein sorting; IMM, inner mitochondrial membrane; LD,
beginning of 2019) showing molecular evidence for lipid droplet; LIR, LC3-interacting region; MAM, mito-
lipid-binding protein modulation of autophagy have chondria-associated membrane; MAP1LC3, microtubule-
been published. We believe that this is just the associated proteins 1A/1B light chain; MTMR3,
beginning of a coordinated effort by the scientific myotubularin-related protein 3; NIPSNAP, 4-nitrophenyl-
community to decipher the role of lipids in autoph- phosphatase domain and nonneuronal SNAP25-like
agy, as basic questions regarding the origin of the protein homolog; NBR1, neighbor of BRCA1 Gene;
NDPK-D, mitochondrial nucleoside diphosphate kinase; autophagy, Mol. Cell 74 (2019) 347–362.e6, https://doi.org/
OMM, outer mitochondrial membrane; OPTN, optineurin; 10.1016/j.molcel.2019.02.010.
PA, phosphatidic acid; PAS, phagophore assembly site; [11] B.J. Ravenhill, K.B. Boyle, N. von Muhlinen, C.J. Ellison, G.
PC, phosphatidylcholine; PDPK1, 3-phosphoinositide- R. Masson, E.G. Otten, A. Foeglein, R. Williams, F.
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Lipids and Lipid-Binding Proteinsin Selective Autophagy

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Lipids and Lipid-Binding Proteinsin Selective Autophagy

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Review

YJMBI-66165; No. of pages: 25; 4C:

Lipids and Lipid-Binding Proteins

Laura R. de la Ballina, Michael J. Munson and Anne Simonsen

Correspondence to Anne Simonsen: anne.simonsen@medisin.uio.no

Introduction Autophagy has been extensively studied over the

Autophagy relies heavily upon membrane dy-

Lipid-binding domains Selective autophagy

Neutral lipids and lipophagy autophagic membrane, the mechanisms linking

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