Journal of Autoimmunity 84 (2017) 21e28

Contents lists available at ScienceDirect

Journal of Autoimmunity
journal homepage: www.elsevier.com/locate/jautimm

SUMO proteins: Guardians of immune system

Sabrina Adorisio a, Alessandra Fierabracci b, Isabella Muscari c, Anna Marina Liberati c,
Emira Ayroldi a, Graziella Migliorati a, Trinh Thi Thuy d, Carlo Riccardi a,
Domenico V. Delfino a, e, *
a
Section of Pharmacology, Department of Medicine, University of Perugia, Piazzale Severi, 06132, Perugia, Italy
b
Type 1 Diabetes Centre, Infectivology and Clinical Trials Research Department, Children's Hospital Bambino Gesù, Rome, Italy
c
Section of Onco-hematology, University of Perugia, Santa Maria Hospital, 05100, Terni, Italy
d
Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Nghia Do, Cau Giay, Ha Noi, Viet Nam
e
Foligno Nursing School, Via Oberdan 123, Foligno, PG, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Small ubiquitin-like modifier (SUMO) proteins belong to the ubiquitin-like family and act to change the
Received 1 August 2017 function of target proteins through post-translational modifications. Through their interactions with innate
Received in revised form immune pathways, SUMOs promote an efficient immune response to pathogenic challenge avoiding, at the
4 September 2017
same time, an excess of immune response that could lead to the development of autoimmune diseases. This
Accepted 4 September 2017
Available online 15 September 2017
report discusses the general functions of SUMO proteins; highlights SUMO involvement in the innate immune
response through their role in NF-kB and interferon pathways; the involvement of SUMO proteins in auto-
immune diseases; and reviews bacterial, viral, and parasitic interactions with SUMO pathways. In conclusion,
Keywords:
Small ubiquitin-like modifier (SUMO)
we speculate that targeting SUMOs could represent a new therapeutic strategy against infections and
proteins autoimmunity.
Innate immune system © 2017 Elsevier Ltd. All rights reserved.
NF-kB pathway
Interferon pathway
Autoimmunity

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2. Role of SUMO in innate immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.1. The NF-kB pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.2. The interferon pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.3. Crosstalk between NF-kB and IFN pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
3. Role of SUMO in autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
4. Role of SUMO during infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
4.1. Bacterial infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
4.2. Viral infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
4.2.1. The PML-nuclear bodies (NB) battle field . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
4.3. Parasitic infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5. Role of SUMO in thymus function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
6. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
6.1. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

* Corresponding author. Section of Pharmacology, Department of Medicine, University of Perugia, Piazzale Severi, 06132, Perugia, Italy.
E-mail address: domenico.delfino@unipg.it (D.V. Delfino).

http://dx.doi.org/10.1016/j.jaut.2017.09.001
0896-8411/© 2017 Elsevier Ltd. All rights reserved.
22 S. Adorisio et al. / Journal of Autoimmunity 84 (2017) 21e28
1. Introduction
Post-translational modifications by small ubiquitin-like modi-
fiers (SUMOs) are crucial in activating protein functions, which lead
to target effects at the molecular, cellular, and systemic levels.
SUMOs belong to the ubiquitin-like (Ubl) family of proteins and are
ubiquitously expressed in eukaryotic cells. Four SUMO isoforms
have been identified, SUMO-1-4, with SUMO-2 and -3 almost
identical in structure [1]. Conjugation of SUMO proteins with target
substrates, sumoylation, resembles the ubiquitination process and
involves three distinct steps. First, SUMO binds to the E1 activating
enzyme, SAE1/SAE2, which results in the activation of SUMO.
Activated SUMO is then transferred to the E2 conjugation enzyme,
Ubc9. Ubc9 then acts to target SUMO to its specific substrate, which
is bound to an E3 ligase (protein inhibitor of activated STAT [PIAS],
Ran binding protein 2 [RanBP2], polycomb protein 2 [Pc2]), through
covalent binding. Sumoylation differs from ubiquitination in the
number of enzymes involved, with less SUMO-related enzymes
known, and that E3 ligation is not always required for SUMO
binding. In the consensus site on the target protein, characterized
by the “JKXE” motif [2], SUMO binds to a lysine and then is
released from the target protein through desumoylation, catalyzed
by SUMO-specific peptidases (SENP1, 2, 3, 5, 6, 7) [3]. Thus,
sumoylation is a dynamic and reversible post-translational modi-
fication process [4].
Although SUMO proteins have no function on their own, they
are capable of modulating the functionality of hundreds of target
proteins, with effects that are diverse and target protein-specific.
Recently, SUMOs' role in the regulation of DNA activities, such as
DNA synthesis and damage repair, has emerged as crucial. For
example, SUMO regulates double-stranded break repair, a process
critically important for maintenance of genome stability [4]. SUMO
is also involved in DNA-protein crosslink repair in yeast [5], binding
to proliferating cell nuclear antigen (PCNA) and signaling the
recruitment of the anti-recombinogenic DNA helicase, Srs2 [6]. In
addition, sumoylation of the phosphatase and tensin homolog
protein (PTEN) is required for the PTEN-dependent DNA damage
response [7].
Sumoylation can occur at multiple points in the same pathway.
Notably, during meiotic homologous recombination, there is a
concomitant sumoylation of many proteins, which are then sub-
sequently desumoylated to shut down the pathway [8]. In partic-
ular, the interference phenomenon of meiotic crossover is
regulated by sumoylation, where topoisomerase II and Red1
sumoylation is a critical control mechanism [9]. Additionally, Ubc9
sumoylation determines the SUMO-modification state of target
proteins, where switching from mono-sumoylation to poly-
sumoylation, results in a change of function, essential for meiotic
cell division [10,11]. Sumoylation events also safeguard somatic cell
identity through repressing transition from one cell type to a
different cell type [12].
Sumoylation regulates many other processes that are important
for cellular function. SUMO influences gene transcription, through
both activation [13] and repression [14]. Intermediate filament
proteins are also modified by SUMO, which are important for
cytoskeleton structural functions and intracellular communications
[15]. SUMO-2 plays a role in repressing the expression of provirus
and endogenous retroviruses by pluripotent stem cells [16].
SUMO modifications have also been implicated in general health
maintenance and systemic disease. Recent discoveries suggest that
sumoylation plays a role in breast cancer [17], melanoma [18], renal
carcinoma [19], and the response to heart failure therapy [20e22].
Given these wide-ranging effects and the importance of SUMO-
dependent processes on health, the remainder of this review will
examine the role of SUMO in the innate immune defense against
pathogens and dissect how SUMO modulation impacts the immune
response to infection and autoimmunity.
2. Role of SUMO in innate immunity
The innate immune response forms the first line of defense
against invading pathogens. One important aspect of innate im-
munity is the recognition of pathogens and microorganisms that
express pathogen-associated molecular patterns (PAMPs) by host
cell pattern recognition receptors (PRRs). Activation of these re-
ceptors triggers signaling pathways that result in the production of
anti-microbial mediators and the initiation of an immune response.
PRR signaling cascades, stemming from both membrane-bound
and intracellular receptors, culminate in the activation of the
transcriptional regulators, nuclear factor kappa-light-chain-
enhancer of activated B cells (NF-kB) or interferon regulatory fac-
tors (IRF) [23].
These pathways are tightly regulated by sumoylation [24,25],
which promotes the production of anti-microbial molecules. SUMO
modifications are also important in the negative regulation of these
pathways, avoiding an excessive immune response that could be
detrimental to the host and lead to the development of autoim-
mune disease or tissue damage. This balance between activation
and resolution of inflammatory cascades is exemplified in the
cellular response to viral infection. Viral DNA is recognized by cyclic
GMP-AMP synthase (cGAS), which results in the activation of the
adaptor protein, stimulator of interferon genes (STING). Tripartite
motif containing 38 (TRIM38), a ubiquitin ligase, sumoylates and
stabilizes cGAS and STING during the early phase of viral infection,
amplifying the antiviral cell response. In the late phase of infection,
cGAS and STING are desumoylated by sentrin-specific protease 2
(Senp2) and subsequently degraded, thus shutting off this pathway
and limiting the immune response to avoid excess activation
[26,27].
2.1. The NF-kB pathway
Among PRRs, Toll-like receptors (TLRs) form the frontline of
immune defense. Upon ligand binding to membrane-bound TLRs, a
signaling cascade is initiated that results in NF-kB activation, the
canonical inflammatory transcription factor (Fig. 1). For example,
when TLR4 recognizes lipopolysaccharide (LPS) on bacterial outer
membranes, this triggers the recruitment of the adaptor protein
myeloid differentiation primary response gene 88 (MyD88) and
signaling molecules interleukin-1 receptor-associated kinases 1
and 4 (IRAK1, 4). IRAK1 and IRAK4 then associate with TNF
receptor-associated factor 6 (TRAF6). TRAF6 activates the down-
stream TAK kinase, which leads to inhibitor of nuclear factor kappa-
B kinase (IKK) complex activation. IKK complex then regulates the
activation state of NF-kB, leading to nuclear translocation and the
transcription of inflammatory cytokines and initiation of the innate
immune response [1].
In this pathway, discussed further below, SUMOs act at different
levels to influence signaling. At the beginning of the cascade, the
Pellino protein associates with IRAK1, resulting in reciprocal
phosphorylation. Pellino-1 is modified by SUMO-1, although the
biological significance of this modification is still unclear [28].
Downstream of IRAK-1/TRAF6, SUMO-1 binds to TRAF family
member-associated NF-kappa-B activator (TANK) and relieves its
repression on TLR signaling. Acting on the IKK complex, SUMO-3
binds to IKK-g (NEMO) which forms a complex with IKKa and
IKKb kinases, that then phosphorylate IkBa, an inhibitor of NF-kB,
leading to its degradation and subsequent NF-kB activation.
SUMO-1 also negatively regulates this pathway through binding
and protecting dephosphorylated IkBa from degradation, thus
 S. Adorisio et al. / Journal of Autoimmunity 84 (2017) 21e28 23

mechanism involved in innate immunity [30,31].

2.2. The interferon pathway

Viruses stimulate an innate immune response by triggering the

production of type I and II interferons (IFNs). IFNs bind to their
receptors, IFN alpha receptor (IFNAR) and IFN gamma receptor
(IFNGR), initiating signal transduction pathways that lead to tran-
scription of interferon-stimulated genes (ISGs) and IFN gamma-
activated site (GAS) genes, which contribute to the antiviral im-
mune response. These pathways are rigorously regulated by
sumoylation at multiple sites. Viral products, such as CpG-rich DNA
and single-stranded (ss)RNA, trigger signaling cascades that lead to
IRF3, IRF7, and IRF8 transcription factor activation, which then
stimulate the transcription of ISGs (Fig. 2). IRF3 sumoylation in-
hibits the IRF3-dependent transcription of IFNb, whereas desu-
moylation, by SENP2, results in ubiquitination and proteasomal
degradation of IRF3, thus removing the IRF3-SUMO-dependent
inhibition of IFN-b transcription [33]. IRF3 is also activated by
sumoylated promyelocytic leukemia protein (PML)-IV. Sumoylated
PML-IV associates with peptidyl-prolyl cis/trans isomerase (Pin1),
preventing Pin1 from binding and degrading IRF3. This leads to an
increased production of IRF3-dependent IFN-b and a resulting
strong antiviral response [34,35]. Therefore, SUMO both promotes
and inhibits antiviral IRF3 activity, through direct binding (inhibi-
tion) and PML-IV sumoylation (promotion) that impedes the Pin1-
dependent degradation of IRF3 (Fig. 2).
IRF7 is phosphorylated and activated through MyD88-
dependent TLR activation, which occurs when intracellular TLR9
and TLR7/8 recognize CpG DNA and ssRNA viral products (Fig. 2).
SUMO binds and inhibits IRF7 phosphorylation, resulting in

Fig. 1. The role of SUMOylation in the NF-kB signaling pathway. SUMOylation and
deSUMOylation of proteins are observed at several steps in this pathway and can both
positively (green) and negatively (red) regulate NF-kB activation.

keeping NF-kB in an inactive state. The detachment of SUMO from

IkBa results in NF-kB activation. In another example of negative NF-
kB regulation, DNA damage induces the desumoylation of NEMO by
SUMO-specific protease 2 (SENP2), resulting in inhibition of NF-kB
activation [29]. We speculate that this mechanism of NF-kB
repression may also occur in response to innate immune signaling
(Fig. 1). Therefore, SUMO proteins play a dual role in the NF-kB
pathway: activation, through the sumoylation of TANK and NEMO,
to mount an efficient innate immune response; and inhibition,
through sumoylation of IkBa, in order to limit excessive activation
[1]. This pathway regulation by SUMO is extremely important.
Either deficient or excessive NF-kB activation may be detrimental to
the host's response against pathogens, leading to a decreased
ability to defend against infection or chronic inflammation that
may promote the development of autoimmune diseases.
NF-kB transcriptional activity is also regulated through inter-
action with nuclear co-repressor (NCoR) complex. TLR signaling
results in the release of NCoR from its DNA binding site, allowing
access for NF-kB binding. However, liver X receptor (LXR) sumoy-
lation, mediated by the E3 SUMO ligase, PIAS1, maintains NCoR
binding, thus repressing NF-kB-mediated transcription [30,31]. The
TLR-dependent de-repression of inflammatory target genes
through NCoR release relies on both the action of coronin 2A
(CORO2A), a component of the NCoR complex, and LXR desumoy-
lation by SENP3. Sumoylated LXRs bind and inhibit CORO2A [32] Fig. 2. The role of SUMOylation in the interferon pathway. SUMOylation and
deSUMOylation of IRF transcription factors can inhibit translation and phosphorylation
(Fig. 1). This regulatory mechanism is involved in the promotion or trigger degradation, respectively. Sumoylation of upstream factors can both activate
of inflammation in atherosclerosis but may also be a general (green) and inhibit (red) IRF transcription factors.
24 S. Adorisio et al. / Journal of Autoimmunity 84 (2017) 21e28
negative regulation of IFN-a expression [1]. Enhancing this
repression, TRIM28 functions as a SUMO E3 enzyme, which
sumoylates IRF7, resulting in transcriptional inhibition of the IFN-a
gene [36]. In addition to TRIM28, another SUMO E3 enzyme, protein
inhibitor of activated STAT-1 (PIAS), inhibits IFN transcription
through SUMO modifications [37] (Fig. 2). IRF8, when bound to
SUMO-2/3, represses the transcription of its antiviral target genes
interleukin (IL)-12 p40 and IFN. Transcription of these genes are
then activated by SENP1-dependent desumoylation of IRF8 [35]
(Fig. 2).
Following production and release, type I and type II IFNs bind to
their receptors on the cell membrane, IFNAR and IFNGR, respec-
tively, and initiate signaling pathways that result in ISG gene
transcription and enhancement of the antiviral immune response.
Specifically, type I IFNs (a and b), bind IFNAR and stimulate the
recruitment of Janus kinase 1 (JAK1) and tyrosine-protein kinase 2
(TYK2), which, in turn, phosphorylate STAT1/STAT2 heterodimers
that form a complex with IRF9 (Fig. 3). This trimeric complex
translocates to the nucleus where it binds to DNA consensus se-
quences, interferon-sensitive response elements (ISRE), promoting
the transcription of ISGs genes. Similarly, when IFN-g, a type II IFN,
binds to its receptor, IFNGR, JAK1/JAK2 are recruited to the receptor
and phosphorylate the STAT1 homodimer. This complex trans-
locates to the nucleus and binds to the DNA consensus sequence
GAS to stimulate the transcription of ISG genes. PML promotes this
pathway by increasing the phosphorylation of STAT1; however,
SUMO-1 binds and inhibits STAT1 phosphorylation.
Whereas STAT1 sumoylation does not affect the type I IFN
pathway, as alternative phosphorylation of the STAT2 homodimer
Fig. 3. The role of SUMOylation in interferon-activated JAK/STAT pathways.
SUMOylation of STAT1 can impair and block gene expression activated by type I and
type II interferons, respectively.
complex occurs, it completely blocks the IFN-g pathway through
inhibiting phosphorylation of the sumoylated homodimer (Fig. 3).
SUMO-1 also binds to PML, however, this sumoylation does not
reduce its STAT1 phosphorylation activity. Similar to SUMO-1,
SUMO-3 also modifies STAT1. However, SUMO-3 binding to PML
results in inhibition rather than reinforcement of STAT1 phos-
phorylation [38]. Therefore, SUMO-1 and SUMO-3 modifications of
STAT1 and PML impair ISG transcription and the IFN-g-mediated
antiviral response, while they do not affect these outcomes for type
I IFNs.
IFN-g-induced gene transcription is also controlled by LXRs. LXR
sumoylation negatively regulates the transcription of the nitric
oxide synthase 2 (NOS) gene, induced by IFN-g, as it decreases
STAT1 recruitment to the gene promoter. Of note, the inhibitory
effect is bidirectional, as IFN-g inhibits LXR-dependent up-regula-
tion of selective gene targets such as ATP-binding cassette A1
(ABCA1) and sterol response element binding protein 1c (SRBP1c)
[39].
2.3. Crosstalk between NF-kB and IFN pathways
SUMO has been implicated in providing balance to the antiviral
response by interfering with both IRF3- and NF-kB-dependent
production of type I IFNs and cytokines. During a viral infection,
viral DNA binds to the cytosolic PRR, retinoic acid-inducible gene-I
(RIG-I), which is sumoylated [40] and activates the mitochondrial
antiviral signaling (MAVS) protein. MAVS then stimulates the NF-kB
and IRF3-dependent production of type I IFNs. This antiviral
response is inhibited by MAVS degradation, which is promoted by
insulin receptor tyrosine kinase substrate (IRTKS)-dependent
sumoylation of poly(rC)-binding protein 2 (PCBP2). Sumoylated
PCBP2 is exported from the nucleus to the cytoplasm where it de-
grades MAVS [34].
3. Role of SUMO in autoimmunity
The importance of SUMO proteins in avoiding excessive immune
response and subsequent autoimmunity is demonstrated by their
involvement in both the regulation of T regulatory (Treg) cell ac-
tivity and the development of different autoimmune diseases. In
the case of CD4þCD25þFoxp3þ Treg cells, selective deletion of Ubc9,
the E2 SUMO-conjugation enzyme, in Tregs results in fatal, early-
onset autoimmunity similar to that seen in Foxp3-mutant mice
[41].
SUMO has been shown to play a role in several autoimmune
diseases, including type 1 diabetes (T1D) [42e47], Bechet's disease
[48], rheumatoid arthritis (RA) [49], gammopathies [50], and
Wiskott-Aldrich syndrome (WAS) [51] (Table 1). T1D is a multi-
factorial autoimmune disease that leads to the destruction of
pancreatic insulin-producing b cells [47]. SUMO4 could play a
central role in T1D. It was initially cloned from the IDDM5 region of
chromosome 6q25 [42], specifically among 55 single-nucleotide
polymorphism markers located in the 16 non-HLA genes geno-
typed to T1D [43]. SUMO4 is known to interact with IkBa and
inhibit NF-kB transcriptional activity. The SUMO4 M55V mutation
prevents the sumoylation of IkBa and subsequent inhibition of NF-
kB. Downstream, this mutation leads to the activation and tran-
scription of genes involved in T1D development [44,45]. Thus, NF-
kB dysregulation through a SUMO4-mediated mechanism could be
an important factor in the pathogenesis of T1D [44e46].
SUMO4 also is involved in HLA-B51-positive Bechet's disease.
The C438T polymorphism of SUMO4 is associated with a signifi-
cantly increased risk of papulopustular skin lesions [48]. In RA, the
SUMO-conjugating enzyme UBC9 may promote the proliferation
and migration of fibroblast-like synoviocytes in affected joints [49].
 S. Adorisio et al. / Journal of Autoimmunity 84 (2017) 21e28 25

Table 1 process in host cells. Here, we will review the literature on SUMO
SUMO involvement in autoimmune and infectious diseases. modifications during bacterial, viral, and parasitic infections
Diseases Pathogens References (Table 1).
Autoimmunity
Type 1 diabetes 42, 43, 44, 45, 46, 47 4.1. Bacterial infection
Bechet's disease 48
Rheumatoid arthritis 49 A landmark finding demonstrating the importance of sumoy-
Gammopathies 50
lation during the host response to bacterial infection, was the dis-
Wiskott-Aldrich syndrome 51
Breast cancer 52 covery of the evasion strategy of Listeria monocytogenes, which
Infections results in a reduction in host cellular sumoylated proteins critical
Bacteria L. monocytogenes 54, 55 for defense against infection, mediated by proteasome-
Shigella 56, 57
independent Ubc9 degradation by the bacterial virulence factor
Xanthomonas euvesicatoria 58, 59
Pseudomonas aeruginosa 60
listeriolysin O (LLO). In vitro studies show that overexpression of
Viruses Kaposi's sarcoma-associated 65, 68, 79, 80, 81 SUMO1 or SUMO2 decreases the number of L. monocytogenes in
herpes virus infected HeLa cells. This demonstrates the importance of sumoy-
Vaccinia virus 66 lation in the resistance of host cells to infective bacteria, as it is
Enterovirus 71 67, 68, 69
detrimental for bacterial invasion and replication [54,55].
Epstein-Barr virus 68, 69, 70, 76
Crimean-Congo 71 Similar to listeria infection, Shigella also impairs the sumoyla-
hemorrhagic fever virus tion process in infected cells. Specifically, like L. monocytogenes,
Vesicular stomatitis virus 72, 73 Shigella dramatically decreases the amount of Ubc9, an E2 conju-
Herpes simplex type 1 virus 75, 82 gating enzyme, and therefore, decreases the amount of sumoylated
Cytomegalovirus 77
Adenovirus 78
proteins important in the host defense against infection. This effect
Parasites Trypanosoma brucei 83 is mediated by the type III secretion system (T3SS), a system that
Shigella uses to deliver effector proteins into the cytosol of infected
human cells [56]. One such effector is OspF, which enters the nu-
In addition, the presence of heat-shock protein 90 (HSP90)-SUMO1 cleus and regulates pro-inflammatory cytokine expression. OspF
is a marker of healthy individuals at risk for plasma cell dyscrasias. translocation into the nucleus is dependent on its sumoylation [56].
Further, the dominant inheritance of this posttranslationally This discovery has important public health implications, as
modified autoantigenic paratarg is one of the strongest molecular- Shigella-dependent diarrheal disease is a major health problem in
level risk factors for developing monoclonal gammopathies of un- the developing world. Increasing protein sumoylation is a potential
determined significance (MGUS), multiple myeloma (MM), and therapeutic strategy against Shigella infection, as Shigella is
Waldenstrom's macroglobulinemia (WM) [50]. becoming increasingly resistant to antibiotic treatment [57].
The role of SUMO in WAS highlights the balancing act between Another interesting bacterial strategy that interferes with
immune and autoimmune response played by SUMO. WAS is an X- sumoylation is described in plants. In tomato plants, Xanthomonas
linked disorder that causes both a deficient immune response and euvescicatoria (Xcv) produces XopD, a type III secretion effector,
autoimmunity. It is caused by mutations in WAS, which encodes that desumoylates the tomato transcription factor SIERF4, thus
Wiskott-Aldrich syndrome protein (WASp). In patients with WAS, repressing the tomato's anti-Xcv immunity, which relies on
autoimmunity is favored over immune response when the SUMO- sumoylated SIERF4 [58,59].
binding site of WASp bears the V75M mutation, one of many In a study analyzing host interactions with Pseudomonas aeru-
disease-causing mutations. This specific mutation compromises ginosa and Streptococcus pneumonia, two of the most common
WASp sumoylation, causing histone deacetylase-6 (HDAC6) to bacteria that cause pneumonia, SUMO1 has been shown to be
upregulate the NF-kB response genes associated with autoimmu- important in defense during infection [60]. This is another example
nity (granulocyte macrophage colony-stimulating factor [GM-CSF], of SUMO proteins that are good therapeutic targets. Like Shigella,
tumor necrosis factor alpha-induced protein 2 [TNFAIP2], IL-1b) but pathogens that cause pneumonia are becoming increasingly resis-
not adaptive immunity (IFNG, STAT1, TLR1) in Th1 cells. Moreover, tance to antibiotics and therefore, new drugs and strategies are
expression of sumoylation-deficient WASp leads to ectopic devel- needed to combat disease [60].
opment of the TH17-like phenotype, which favors the development
of WAS-associated autoimmune manifestations [51]. 4.2. Viral infection
SUMO-related autoimmunity may contribute to certain cancers.
The presence of autoantibodies to SUMO peptidase 2 and other As seen in bacteria, viruses also interfere with SUMO pathways
important centrosome antigens have been shown to be associated as a strategy to evade the host immune system. Many viruses have
with breast cancer, suggesting that alterations in sumoylation could been identified which disrupt SUMO modifications (Table 1). These
be related to the development of autoimmunity in breast cancer include the chick embryo lethal orphan (CELO) virus, geminivirus,
patients [52]. SUMOs also are important regulators of autoimmu- adenovirus, Kaposi's sarcoma-associated herpes virus (KSHV),
nity in plants. For example, the SUMO E3 ligase siz1 regulates vaccinia virus (VACV), bovine papillomavirus, human papilloma-
numerous processes, including immune response, in Arabidopsis. A virus, Moloney murine leukemia virus, influenza A virus, cyto-
loss-of-function mutation in siz1 produces an autoimmune megalovirus, Epstein-Barr virus (EBV), Hantaan virus, Mason-Pfizer
phenotype [53]. Thus, SUMO proteins are critical molecules that virus, human immunodeficiency virus, Ebola Zaire virus, herpes
can control autoimmunity development. simplex type 1 virus, varicella zoster virus, and encephalomyocar-
ditis virus [61] and others, described in more detail below (see
4. Role of SUMO during infection Table 1). Viruses disrupt sumoylation through two established
ways: 1) various viral proteins are sumoylated to exploit the host
The importance of sumoylation in the immune response during SUMO machinery; and 2) they interfere with the sumoylation of
infection is highlighted by the development of pathogen strategies host immune defense proteins, through desumoylation (targeting
that aim to evade host defense by impairing the sumoylation SUMOs and sumoylated proteins for ubiquitin-mediated
26 S. Adorisio et al. / Journal of Autoimmunity 84 (2017) 21e28
degradation) or sumoylation. The ultimate goal of both strategies is
to decrease the host innate immune response [62e64].
KSHV employs the first strategy to produce a transcriptional
repressor called K-bZIP, which interferes with the type I IFN
pathway when sumoylated, without E3-SUMO ligase activity [65].
VACV exploits the host cell SUMO conjugation system to induce a
covalent interaction between the E3 protein and SUMO1 or SUMO2.
This results in modifications that repress E3 transcriptional regu-
lation of p53-upregulated modulator of apoptosis (PUMA) and
apoptotic protease activating factor 1 (APAF-1) genes [66]. More-
over, during enterovirus 71 infection, polymerase 3D sumoylation
facilitates virus replication and infection, leading to fatal neuro-
logical diseases in children [67e69].
With regard to the second strategy, various viruses acquire the
ability to sumoylate host proteins. EBV latent membrane protein 1
(LMP1) sumoylates IRF7, limiting its function in initiating an effi-
cient innate immune response [68e70]. In hepatocytes infected
with Crimean-Congo hemorrhagic fever virus (CCHFV), there is an
up-regulation of SUMO-E1 enzyme (SAE2/UBA2), although the
exact role of sumoylation remains to be clarified [71]. In addition,
viruses, such as vesicular stomatitis virus (VSV), promote them-
selves through inducing p53 sumoylation. This modification leads
to cellular senescence, which favors viral replication [72].
Host cells also use sumoylation to regulate and activate the
immune response against infection. One example is the increased
resistance of human cells to VSV infection due to SUMO-dependent
degradation protection of the human MxA protein, a member of the
large dynamin-like GTPase family. MxA is stabilized by SUMO and
inhibits VSV primary transcription. This effect is VSV-specific as
SUMO actually renders cells more sensitive to the rabies virus
(RABV) [73].
It is interesting to examine the differential role of SUMO-1 and
SUMO-2/3 during viral reactivation. Chromatin occupancy of
SUMO-2/3, but not of SUMO-1, is increased during viral reactivation
in transcription factor binding regions. This suggests a role for
SUMO-2/3 in host-mediated suppression of gene expression [74]. In
another study, a comprehensive analysis of cellular proteins whose
sumoylation state was altered during HSV1 infection showed that
sumoylation was reduced in 124 proteins. Among these, several
proteins were targets of infected cell protein 0 (ICP0), which
functions as an E3 ubiquitin ligase, targeting proteins for ubiquiti-
nation and degradation with putative repressive activity [75].
A fascinating emerging strategy employed by viruses to evade
the host immune response is through coding microRNAs (miRNAs).
A recent study identified miRNAs encoded by EBV that interfere
with the SUMO signaling network of the host, that influence the
immune response, such as PML, IRF1, Sp100, HLA-B, MX-1, ADAR,
OAS3, RNF4, and STAT6 [76].
4.2.1. The PML-nuclear bodies (NB) battle field
An exemplification of the fight between viruses and host cells, in
which SUMO has a starring role, is the viral interference with
protein sumoylation in the context of PML-NB. Recently it has been
shown, that host cells have the ability to counterattack viruses by
sumoylating viral proteins within PML-NBs. For example, the ND10
component of PML proteins sumoylates the major immediate early
protein IE1p72 of human cytomegalovirus, thus compromising its
interferon-antagonistic function [77]. Different PML-NBs-
associated proteins are sumoylated by SUMO-1, within the
external NB formed by PML and Sp100, and SUMO-2/3, within the
internal NB. Adenovirus disrupt this antiviral mechanism through
transactivator protein E1A, which targets PML-II and promotes viral
and cellular transcription. Adenovirus also induce the detachment
of SUMO-2/3 from Sp100A, thus impeding its association with
heterochromatin protein 1 (HP1), a repressive factor. As a
consequence, Sp100A, within PML-NBs, create a permissive envi-
ronment for viral replication [78]. In addition, KSHV encodes
SUMO-targeting E3 ubiquitin ligase (STUbL), K-Rta, which targets
sumoylated PML involved in virus replication inhibition for
ubiquitin-mediated degradation [68,79].
KSHV utilize at least other two proteins to dampen the SUMO-
dependent host immune response. Viral (v)IRF3 promotes the
SUMO-dependent ubiquitination and degradation of PML and vPK
catalyzes the phosphorylation-dependent sumoylation of the
transcriptional repressors K-bZIP and KAP-1. Additional sumoylated
proteins are also involved in the KSHV evasion of host defense
mechanisms and all of them, including ORF7, interfere with the
assembly of PML-NBs [80]. KSHV also encodes latency-associated
nuclear antigen (LANA), a multifunctional protein that interacts
with chromatin factors. LANA displaces Sp100 from chromatin and
relocalizes it in PML-NBs by enhancing SUMO-1 and SUMO-2
binding [81].
PML-NBs are also the targets of herpes simplex virus 1 (HSV-1),
although by a different mechanism. HSV-1 encodes ICP0, an E3
ubiquitin ligase, that targets proteins for ubiquitination and
consequent degradation, which is required for efficient viral repli-
cation. In the PML-NB, ICP0 desumoylates PML-NB proteins
involved in repression, decreasing the overall level of SUMO-
conjugated proteins in the infected cells and allowing a permis-
sive environment for viral replication [82].
4.3. Parasitic infection
Parasites have an original mechanism to avoid the host immune
response by exploiting SUMO. Trypanosoma brucei displays the
variant surface glycoprotein (VSG) on its surface, which allows the
parasite to evade detection by extensive antigenic variation. Try-
panosoma brucei express only one VSG variant among approxi-
mately 1000 VSG genes, allowing it to avoid the host immune
antibody response. This monoallelic expression of VSG is a result of
SUMO, which associates with the VSG chromatin region and the
nuclear body ESB. Sumoylation of chromatin-associated proteins
determines the recruitment of RNA polymerase I to the VSG pro-
moter. This suggests that sumoylation is involved in VSG mono-
allelic expression [83].
5. Role of SUMO in thymus function
Along with the bone marrow, the thymus is the primary
lymphoid organ where T lymphocyte maturation is completed.
Therefore, the thymus plays an important role in the defense
against pathogens. During infections, the thymus undergoes
reversible involution [84]. Glucocorticoids (GCs) are involved in
thymic involution by triggering massive thymocyte apoptosis. To
this end, GCs stimulate the transcription of glucocorticoid-induced
leucine zipper (Gilz) and the activation of caspase-8, which, in turn,
co-activate each other. Gilz activates caspase-8 and activated
caspase-8 sumoylates Gilz, allowing the prolongation of Gilz
expression by inhibiting ubiquitin-mediated Gilz proteasomal
degradation. The final result of this process is apoptosis of thy-
mocytes [85,86].
6. Discussion
SUMO molecules bind to target proteins and modulate their
function. The goal of this review was to highlight how SUMO plays a
crucial role in innate immunity, reviewing the latest findings on
SUMO's influence during the innate immune response and
infection.
From the findings reported, three important points emerged: 1)
 S. Adorisio et al. / Journal of Autoimmunity 84 (2017) 21e28
SUMO proteins act at multiple sites in a pathway and often, the
sumoylation of all these sites is necessary for the function of that
particular pathway; 2) SUMOs are able to enhance signaling that
initiates an immune response, but also are important in resolving
inflammation, allowing a balanced response; 3) SUMOs are
important molecules in defense against infections, as pathogens
interfere with sumoylation of host molecules to evade an immune
response.
During an innate immune response, SUMO proteins influence
both the NF-kB and IFNs pathways, the two major innate immune
pathways, at multiple levels. As has been shown for SUMO-
dependent homologous recombination, concurrent SUMO modifi-
cations are necessary for the proper functioning of each immune
pathway. In addition, SUMO function during an immune response
varies, being important in both increasing the activation of innate
immune signaling pathways through sumoylation, and decreasing
the innate immune response through desumoylation or binding to
inhibitory proteins. This dual-action contributes to a balanced and
well-regulated immune response that is capable of protection
against foreign pathogens, but at the same time, prevented from an
exaggerated response, involving the risk of autoimmunity and tis-
sue damage. Type 1 diabetes development is, in fact, partly a
consequence of SUMO-NEMO-dependent augmentation of NF-kB
activity [46]. Thus, the SUMO system must strictly control immune
signaling pathway activation.
6.1. Conclusions
The importance of sumoylation in autoimmunity is highlighted
by the involvement of SUMO proteins in the development of
different autoimmune diseases and its importance in defense
against pathogens. For example, bacteria, viruses, and parasites
interfere with the sumoylation of host cells by exploiting the host
system to enable sumoylation of their own proteins and by inter-
fering with sumoylation of host proteins. Both strategies lead to a
decreased immune defense or detection, which increasing their
infective potential. The pivotal role of SUMO in modulation of the
immune system suggests that new therapeutic strategies for
treating autoimmune diseases and infections that target SUMO are
warranted, especially the latter given the rapid increase in micro-
bial resistance to antibiotics [87]. Therefore, SUMOs could be a
novel target in the fight against infectious and autoimmune
diseases.
Funding
This work was supported by the Italian “Ministero degli Esteri e
della Cooperazione Internazionale” (MAECI); “Associazione Italiana
per la ricerca contro il cancro” (AIRC); and Vietnam Ministry of
Science and Technology (MOST).
Acknowledgements
We thank BioScience Writers for editing assistance.
References
[1] X. Liu, Q. Wang, W. Chen, C. Wang, Dynamic regulation of innate immunity by
ubiquitin and ubiquitin-like proteins, Cytokine & Growth Factor Rev. 24
(2013) 559e570.
[2] I.A. Hendriks, A.C. Vertegaal, A high-yield double-purification proteomics
strategy for the identification of SUMO sites, Nat. Protoc. 11 (2016)
1630e1649.
[3] C.M. Hickey, N.R. Wilson, M. Hochstrasser, Function and regulation of SUMO
proteases, Nat. Rev. Mol. Cell Biol. 13 (2012) 755e766.
[4] P. Schwertman, S. Bekker-Jensen, N. Mailand, Regulation of DNA double-
strand break repair by ubiquitin and ubiquitin-like modifiers, Nat. Rev. Mol.
27
Cell Biol. 17 (2016) 379e394.
[5] J. Stingele, M.S. Schwarz, N. Bloemeke, P.G. Wolf, S. Jentsch, A DNA-dependent
protease involved in DNA-protein crosslink repair, Cell 158 (2014) 327e338.
[6] A.A. Armstrong, F. Mohideen, C.D. Lima, Recognition of SUMO-modified PCNA
requires tandem receptor motifs in Srs2, Nature 483 (2012) 59e63.
[7] C. Bassi, J. Ho, T. Srikumar, R.J. Dowling, C. Gorrini, S.J. Miller, et al., Nuclear
PTEN controls DNA repair and sensitivity to genotoxic stress, Science 341
(2013) 395e399.
[8] I. Psakhye, S. Jentsch, Protein group modification and synergy in the SUMO
pathway as exemplified in DNA repair, Cell 151 (2012) 807e820.
[9] L. Zhang, S. Wang, S. Yin, S. Hong, K.P. Kim, N. Kleckner, Topoisomerase II
mediates meiotic crossover interference, Nature 511 (2014) 551e556.
[10] M. Dasso, Biochemistry: rear view of an enzyme, Nature 497 (2013) 576e577.
[11] H. Klug, M. Xaver, V.K. Chaugule, S. Koidl, G. Mittler, F. Klein, et al., Ubc9
sumoylation controls SUMO chain formation and meiotic synapsis in
Saccharomyces cerevisiae, Mol. Cell 50 (2013) 625e636.
[12] S. Cheloufi, U. Elling, B. Hopfgartner, Y.L. Jung, J. Murn, M. Ninova, et al., The
histone chaperone CAF-1 safeguards somatic cell identity, Nature 528 (2015)
218e224.
[13] L. Yang, C. Lin, W. Liu, J. Zhang, K.A. Ohgi, J.D. Grinstein, et al., ncRNA- and Pc2
methylation-dependent gene relocation between nuclear structures mediates
gene activation programs, Cell 147 (2011) 773e788.
[14] P.A. Dutchak, T. Katafuchi, A.L. Bookout, J.H. Choi, R.T. Yu, D.J. Mangelsdorf, et
al., Fibroblast growth factor-21 regulates PPARgamma activity and the anti-
diabetic actions of thiazolidinediones, Cell 148 (2012) 556e567.
[15] N.T. Snider, M.B. Omary, Post-translational modifications of intermediate
filament proteins: mechanisms and functions, Nat. Rev. Mol. Cell Biol. 15
(2014) 163e177.
[16] B.X. Yang, C.A. El Farran, H.C. Guo, T. Yu, H.T. Fang, H.F. Wang, et al., Systematic
identification of factors for provirus silencing in embryonic stem cells, Cell
163 (2015) 230e245.
[17] J.D. Kessler, K.T. Kahle, T. Sun, K.L. Meerbrey, M.R. Schlabach, E.M. Schmitt, et
al., A SUMOylation-dependent transcriptional subprogram is required for
Myc-driven tumorigenesis, Science 335 (2012) 348e353.
[18] S. Yokoyama, S.L. Woods, G.M. Boyle, L.G. Aoude, S. MacGregor, V. Zismann, et
al., A novel recurrent mutation in MITF predisposes to familial and sporadic
melanoma, Nature 480 (2011) 99e103.
[19] C. Bertolotto, F. Lesueur, S. Giuliano, T. Strub, M. de Lichy, K. Bille, et al.,
A SUMOylation-defective MITF germline mutation predisposes to melanoma
and renal carcinoma, Nature 480 (2011) 94e98.
[20] C. Kho, A. Lee, D. Jeong, J.G. Oh, A.H. Chaanine, E. Kizana, et al., SUMO1-
dependent modulation of SERCA2a in heart failure, Nature 477 (2011)
601e605.
[21] S.K. Shenoy, H.A. Rockman, Cardiovascular biology: heart fails without pump
partner, Nature 477 (2011) 546e547.
[22] J.J. McMurray, G.L. Smith, Calcium handling in the failing heart and
SUMOeweighing the evidence, N. Engl. J. Med. 365 (2011) 1738e1739.
[23] K. Chen, J. Liu, X. Cao, Regulation of type I interferon signaling in immunity
and inflammation: a comprehensive review, J. Autoimmun. 83 (2017) 1e11.
[24] Z. Hannoun, G. Maarifi, M.K. Chelbi-Alix, The implication of SUMO in intrinsic
and innate immunity, Cytokine & Growth Factor Rev. 29 (2016) 3e16.
[25] J. Liu, C. Qian, X. Cao, Post-translational modification control of innate im-
munity, Immunity 45 (2016) 15e30.
[26] M.M. Hu, Q. Yang, X.Q. Xie, C.Y. Liao, H. Lin, T.T. Liu, et al., Sumoylation pro-
motes the stability of the DNA sensor cGAS and the adaptor STING to regulate
the kinetics of response to DNA virus, Immunity 45 (2016) 555e569.
[27] M.M. Hu, H.B. Shu, Multifaceted roles of TRIM38 in innate immune and in-
flammatory responses, Cell. Mol. Immunol. 14 (2017) 331e338.
[28] J.H. Kim, K.S. Sung, S.M. Jung, Y.S. Lee, J.Y. Kwon, C.Y. Choi, et al., Pellino-1, an
adaptor protein of interleukin-1 receptor/toll-like receptor signaling, is
sumoylated by Ubc9, Mol. Cells 31 (2011) 85e89.
[29] M.H. Lee, A.M. Mabb, G.B. Gill, E.T. Yeh, S. Miyamoto, NF-kappaB induction of
the SUMO protease SENP2: a negative feedback loop to attenuate cell survival
response to genotoxic stress, Mol. Cell 43 (2011) 180e191.
[30] Y. Zhang, Z. Gan, P. Huang, L. Zhou, T. Mao, M. Shao, et al., A role for protein
inhibitor of activated STAT1 (PIAS1) in lipogenic regulation through
SUMOylation-independent suppression of liver X receptors, J. Biol. Chem. 287
(2012) 37973e37985.
[31] S.S. Im, T.F. Osborne, Liver x receptors in atherosclerosis and inflammation,
Circ. Res. 108 (2011) 996e1001.
[32] W. Huang, S. Ghisletti, K. Saijo, M. Gandhi, M. Aouadi, G.J. Tesz, et al., Coronin
2A mediates actin-dependent de-repression of inflammatory response genes,
Nature 470 (2011) 414e418.
[33] Y. Ran, T.T. Liu, Q. Zhou, S. Li, A.P. Mao, Y. Li, et al., SENP2 negatively regulates
cellular antiviral response by deSUMOylating IRF3 and conditioning it for
ubiquitination and degradation, J. Mol. Cell Biol. 3 (2011) 283e292.
[34] P. Xia, S. Wang, Z. Xiong, B. Ye, L.Y. Huang, Z.G. Han, et al., IRTKS negatively
regulates antiviral immunity through PCBP2 sumoylation-mediated MAVS
degradation, Nat. Commun. 6 (2015) 8132.
[35] T.H. Chang, S. Xu, P. Tailor, T. Kanno, K. Ozato, The small ubiquitin-like
modifier-deconjugating enzyme sentrin-specific peptidase 1 switches IFN
regulatory factor 8 from a repressor to an activator during macrophage acti-
vation, J. Immunol. 189 (2012) 3548e3556.
[36] Q. Liang, H. Deng, X. Li, X. Wu, Q. Tang, T.H. Chang, et al., Tripartite motif-
containing protein 28 is a small ubiquitin-related modifier E3 ligase and
28 S. Adorisio et al. / Journal of Autoimmunity 84 (2017) 21e28
negative regulator of IFN regulatory factor 7, J. Immunol. 187 (2011)
4754e4763.
[37] T. Kubota, M. Matsuoka, S. Xu, N. Otsuki, M. Takeda, A. Kato, et al., PIASy in-
hibits virus-induced and interferon-stimulated transcription through distinct
mechanisms, J. Biol. Chem. 286 (2011) 8165e8175.
[38] G. Maarifi, M.A. Maroui, J. Dutrieux, L. Dianoux, S. Nisole, M.K. Chelbi-Alix,
Small ubiquitin-like modifier alters IFN response, J. Immunol. 195 (2015)
2312e2324.
[39] M. Pascual-Garcia, L. Rue, T. Leon, J. Julve, J.M. Carbo, J. Matalonga, et al.,
Reciprocal negative cross-talk between liver X receptors (LXRs) and STAT1:
effects on IFN-gamma-induced inflammatory responses and LXR-dependent
gene expression, J. Immunol. 190 (2013) 6520e6532.
[40] K. Doiron, V. Goyon, E. Coyaud, S. Rajapakse, B. Raught, H.M. McBride, The
dynamic interacting landscape of MAPL reveals essential functions for
SUMOylation in innate immunity, Sci. Rep. 7 (2017) 107.
[41] X. Ding, S. Jin, Y. Tong, X. Jiang, Z. Chen, S. Mei, et al., TLR4 signaling induces
TLR3 up-regulation in alveolar macrophages during acute lung injury, Sci. Rep.
7 (2017) 34278.
[42] J. Zhang, Z. Chen, Z. Zhou, P. Yang, C.Y. Wang, Sumoylation modulates the
susceptibility to type 1 diabetes, Adv. Exp. Med. Biol. 963 (2017) 299e322.
[43] C. Sun, H. Wei, X. Chen, Z. Zhao, H. Du, W. Song, et al., ERBB3-rs2292239 as
primary type 1 diabetes association locus among non-HLA genes in Chinese,
Meta Gene 9 (2016) 120e123.
[44] K.W. Hwang, T.J. Won, H. Kim, H.J. Chun, T. Chun, Y. Park, Characterization of
the regulatory roles of the SUMO, Diabetes/Metab. Res. Rev. 27 (2011)
854e861.
[45] K.W. Hwang, T.J. Won, H. Kim, H.J. Chun, T. Chun, Y. Park, Erratum to 'Char-
acterization of the regulatory roles of the SUMO, Diabetes/Metab. Res. Rev. 28
(2012) 196e202.
[46] L. Shao, B. Feng, Y. Zhang, H. Zhou, W. Ji, W. Min, The role of adipose-derived
inflammatory cytokines in type 1 diabetes, Adipocyte 5 (2016) 270e274.
[47] D. Sireesh, E. Bhakkiyalakshmi, K.M. Ramkumar, S. Rathinakumar,
P.S. Jennifer, P. Rajaguru, et al., Targeting SUMOylation cascade for diabetes
management, Curr. Drug Targets 15 (2014) 1094e1106.
[48] G. Park, H.S. Kim, J.Y. Choe, S.K. Kim, SUMO4 C438T polymorphism is asso-
ciated with papulopustular skin lesion in Korean patients with Behcet's dis-
ease, Rheumatol. Int. 32 (2012) 3031e3037.
[49] F. Li, X. Li, L. Kou, Y. Li, F. Meng, F. Ma, SUMO-conjugating enzyme UBC9
promotes proliferation and migration of fibroblast-like synoviocytes in
rheumatoid arthritis, Inflammation 37 (2014) 1134e1141.
[50] K.D. Preuss, M. Pfreundschuh, M. Weigert, N. Fadle, E. Regitz, B. Kubuschok,
Sumoylated HSP90 is a dominantly inherited plasma cell dyscrasias risk fac-
tor, J. Clin. Investig. 125 (2015) 316e323.
[51] K. Sarkar, S. Sadhukhan, S.S. Han, Y.M. Vyas, SUMOylation-disrupting WAS
mutation converts WASp from a transcriptional activator to a repressor of NF-
kappaB response genes in T cells, Blood 126 (2015) 1670e1682.
[52] M.C. Maroun, O. Olivero, L. Lipovich, A. Stark, L. Tait, S. Bandyopadhyay, et al.,
Anti-centrosome antibodies in breast cancer are the expression of autoim-
munity, Immunol. Res. 60 (2014) 339e347.
[53] M. Gou, Q. Huang, W. Qian, Z. Zhang, Z. Jia, J. Hua, Sumoylation E3 ligase SIZ1
modulates plant immunity partly through the immune receptor gene SNC1 in
Arabidopsis, Mol. Plant-Microbe Interact. MPMI 30 (2017) 334e342.
[54] D. Ribet, M. Hamon, E. Gouin, M.A. Nahori, F. Impens, H. Neyret-Kahn, et al.,
Listeria monocytogenes impairs SUMOylation for efficient infection, Nature
464 (2010) 1192e1195.
[55] H. Pillich, T. Chakraborty, M.A. Mraheil, Cell-autonomous responses in Listeria
monocytogenes infection, Future Microbiol. 10 (2015) 583e597.
[56] K. Jo, E.J. Kim, H.J. Yu, C.H. Yun, D.W. Kim, Host cell nuclear localization of
Shigella flexneri effector OspF is facilitated by SUMOylation, J. Microbiol.
Biotechnol. 27 (2017) 610e615.
[57] S.M. Sidik, J. Salsman, G. Dellaire, J.R. Rohde, Shigella infection interferes with
SUMOylation and increases PML-NB number, PLoS One 10 (2015), e0122585.
[58] J.G. Kim, W. Stork, M.B. Mudgett, Xanthomonas type III effector XopD desu-
moylates tomato transcription factor SlERF4 to suppress ethylene responses
and promote pathogen growth, Cell Host Microbe 13 (2013) 143e154.
[59] C.M. Tan, M.Y. Li, P.Y. Yang, S.H. Chang, Y.P. Ho, H. Lin, et al., Arabidopsis HFR1
is a potential nuclear substrate regulated by the Xanthomonas type III effector
XopD(Xcc8004), PLoS One 10 (2015), e0117067.
[60] S.B. Smith, M. Magid-Slav, J.R. Brown, Host response to respiratory bacterial
pathogens as identified by integrated analysis of human gene expression data,
PLoS One 8 (2013), e75607.
[61] D. Mattoscio, C.V. Segre, S. Chiocca, Viral manipulation of cellular protein
conjugation pathways: the SUMO lesson, World J. Virol. 2 (2013) 79e90.
[62] V.G. Wilson, Sumoylation at the host-pathogen interface, Biomolecules 2
(2012) 203e227.
[63] R.D. Everett, C. Boutell, B.G. Hale, Interplay between viruses and host
sumoylation pathways, Nat. Rev. Microbiol. 11 (2013) 400e411.
[64] L. Chen, S. Li, Y. Li, X. Duan, B. Liu, I. McGilvray, Ubiquitin-like protein mod-
ifiers and their potential for antiviral and anti-HCV therapy, Expert Rev.
Proteom. 10 (2013) 275e287.
[65] S. Lefort, A. Gravel, L. Flamand, Repression of interferon-alpha stimulated
genes expression by Kaposi's sarcoma-associated herpesvirus K-bZIP protein,
Virology 408 (2010) 14e30.
[66] J. Gonzalez-Santamaria, M. Campagna, M.A. Garcia, L. Marcos-Villar,
D. Gonzalez, P. Gallego, et al., Regulation of vaccinia virus E3 protein by small
ubiquitin-like modifier proteins, J. Virol. 85 (2011) 12890e12900.
[67] S. Liu, J. Long, B. Yuan, M. Zheng, M. Xiao, J. Xu, et al., SUMO modification
reverses inhibitory effects of smad nuclear interacting Protein-1 in TGF-beta
responses, J. Biol. Chem. 291 (2016) 24418e24430.
[68] P.C. Chang, M. Campbell, E.S. Robertson, Human oncogenic herpesvirus and
post-translational modifications - phosphorylation and SUMOylation, Front.
Microbiol. 7 (2016) 962.
[69] J. Gan, N. Qiao, R. Strahan, C. Zhu, L. Liu, S.C. Verma, et al., Manipulation of
ubiquitin/SUMO pathways in human herpesviruses infection, Rev. Med. Virol.
26 (2016) 435e445.
[70] G.L. Bentz, J. Shackelford, J.S. Pagano, Epstein-Barr virus latent membrane
protein 1 regulates the function of interferon regulatory factor 7 by inducing
its sumoylation, J. Virol. 86 (2012) 12251e12261.
[71] C. Fraisier, R. Rodrigues, V. Vu Hai, M. Belghazi, S. Bourdon, G. Paranhos-
Baccala, et al., Hepatocyte pathway alterations in response to in vitro Crimean
Congo hemorrhagic fever virus infection, Virus Res. 179 (2014) 187e203.
[72] L. Marcos-Villar, J.V. Perez-Giron, J.M. Vilas, A. Soto, C.F. de la Cruz-Hererra,
V. Lang, et al., SUMOylation of p53 mediates interferon activities, Cell Cycle 12
(2013) 2809e2816.
[73] G. Maarifi, Z. Hannoun, M.C. Geoffroy, F. El Asmi, K. Zarrouk, S. Nisole, et al.,
MxA mediates SUMO-induced resistance to vesicular stomatitis virus, J. Virol.
90 (2016) 6598e6610.
[74] P.C. Chang, C.Y. Cheng, M. Campbell, Y.C. Yang, H.W. Hsu, T.Y. Chang, et al., The
chromatin modification by SUMO-2/3 but not SUMO-1 prevents the epige-
netic activation of key immune-related genes during Kaposi's sarcoma asso-
ciated herpesvirus reactivation, BMC Genomics 14 (2013) 824.
[75] E. Sloan, M.H. Tatham, M. Groslambert, M. Glass, A. Orr, R.T. Hay, et al.,
Analysis of the SUMO2 proteome during HSV-1 infection, PLoS Pathog. 11
(2015), e1005059.
[76] S. Callegari, S. Gastaldello, O.R. Faridani, M.G. Masucci, Epstein-Barr virus
encoded microRNAs target SUMO-regulated cellular functions, FEBS J. 281
(2014) 4935e4950.
[77] N. Reuter, E.M. Schilling, M. Scherer, R. Muller, T. Stamminger, The ND10
component promyelocytic leukemia protein acts as an E3 ligase for SUMOy-
lation of the major immediate early protein IE1 of human cytomegalovirus,
J. Virol. (2017) 91.
[78] J. Berscheminski, P. Wimmer, J. Brun, W.H. Ip, P. Groitl, T. Horlacher, et al.,
Sp100 isoform-specific regulation of human adenovirus 5 gene expression,
J. Virol. 88 (2014) 6076e6092.
[79] Y. Izumiya, K. Kobayashi, K.Y. Kim, M. Pochampalli, C. Izumiya, B. Shevchenko,
et al., Kaposi's sarcoma-associated herpesvirus K-Rta exhibits SUMO-targeting
ubiquitin ligase (STUbL) like activity and is essential for viral reactivation,
PLoS Pathog. 9 (2013), e1003506.
[80] P.C. Chang, H.J. Kung, SUMO and KSHV replication, Cancers 6 (2014)
1905e1924.
[81] T. Gunther, S. Schreiner, T. Dobner, U. Tessmer, A. Grundhoff, Influence of
ND10 components on epigenetic determinants of early KSHV latency estab-
lishment, PLoS Pathog. 10 (2014), e1004274.
[82] Z. Mi, J. Fu, Y. Xiong, H. Tang, SUMOylation of RIG-I positively regulates the
type I interferon signaling, Protein & Cell 1 (2010) 275e283.
[83] D. Lopez-Farfan, J.M. Bart, D.I. Rojas-Barros, M. Navarro, SUMOylation by the
E3 ligase TbSIZ1/PIAS1 positively regulates VSG expression in Trypanosoma
brucei, PLoS Pathog. 10 (2014), e1004545.
[84] N. Pozzesi, A. Fierabracci, T.T. Thuy, M.P. Martelli, A.M. Liberati, E. Ayroldi, et
al., Pharmacological modulation of caspase-8 in thymus-related medical
conditions, J. Pharmacol. Exp. Ther. 351 (2014) 18e24.
[85] D.V. Delfino, S. Spinicelli, N. Pozzesi, S. Pierangeli, E. Velardi, S. Bruscoli, et al.,
Glucocorticoid-induced activation of caspase-8 protects the glucocorticoid-
induced protein Gilz from proteasomal degradation and induces its binding
to SUMO-1 in murine thymocytes, Cell Death Differ. 18 (2011) 183e190.
[86] N. Pozzesi, A. Fierabracci, A.M. Liberati, M.P. Martelli, E. Ayroldi, C. Riccardi, et
al., Role of caspase-8 in thymus function, Cell Death Differ. 21 (2014)
226e233.
[87] D.R. Dodds, Antibiotic resistance: a current epilogue, Biochem. Pharmacol. 134
(2017) 139e146.