DNA AND CELL BIOLOGY

Volume 34, Number 11, 2015

Mary Ann Liebert, Inc.
Pp. 19
DOI: 10.1089/dna.2015.2933

REVIEW ARTICLE

DeSUMOylation:
An Important Therapeutic Target
and Protein Regulatory Event
Chun-Jie Huang, Di Wu, Faheem Ahmed Khan, and Li-Jun Huo

The discovery of the process of small ubiquitin-like modifier (SUMO)-mediated post-translational modification
of targets (SUMOylation) in early 1990s proved to be a significant step ahead in understanding mechanistic
regulation of proteins and their functions in diverse life processes at the cellular level. The critical step in
reversing the SUMOylation pathway is its ability to be dynamically deSUMOylated by SUMO/Sentrin-specific
protease (SENP). This review is intended to give a brief introduction about the process of SUMOylation,
different mammalian deSUMOylating enzymes with special emphasis on their regulation of ribosome biogenesis at the molecular level, and its emerging roles in mitochondrial dynamics that might reveal usefulness of
SENPs for therapeutic applications.

prisingly, a single amino acid mutation modulates preSUMO4 amenable to SENP processing (Wang et al., 2008;
Liu et al., 2014),

Introduction

he physiochemical properties of proteins such as

localization, degradation, and their functions are extensively regulated by post-translational modifications, suggesting proteome complexity. SUMOylation is one of the
most dynamic post-translational modifications with a diverse
repertoire of effects attributable to tag lysine residues on
target proteins with small ubiquitin-like modifier (SUMO)
isoforms, of which functional implications have been widely
determined in almost every aspect of biological processes
(Nacerddine et al., 2005; Hwang et al., 2009; Wang et al.,
2010; Finkbeiner et al., 2011; Lomel and Vazquez, 2011;
Bettermann et al., 2012; Sutinen et al., 2014).
SUMOs belong to a family of ubiquitin-related modifiers
that are covalently bonded and post-translationally conjugated to various substrates (Oh and Chung, 2012). In invertebrates, only one member of SUMO named Smt3 is
expressed, while four different paralogs are reported in
vertebrates named SUMO-1 to SUMO-4 (Lomel and Vazquez, 2011). SUMO-1 plays a key role in regulating cardiac
functions and shares 45% homology with SUMO-2/3
(Krumova and Weishaupt, 2013). SUMO-2 and SUMO-3
can be referred to SUMO-2/3 as they share *97% sequence
homology and usually function as polymeric chains (Yang
and Chiang, 2013). SUMO-4 is mainly expressed in immune
cells and its biological relevance still remains elusive as it is
nonconjugatable under physiological conditions and is not
processed by any identified endogenous sentrin-specific
protease (SENP) (Mukhopadhyay and Dasso, 2007). Sur-

Properties of the deSUMOylation proteases

The process of SUMOylation has dynamic reversible

activity, and a rapid modification at even a small portion of
target proteins is sufficient to produce tremendous functional changes (Hay, 2005). Therefore, a distinctive pattern
of SUMO conjugates is always observed during the cell
cycle (Kolli, et al., 2010). The reversible modification is due
to the action of proteases, which remove attached molecules
from the substrate as well as are responsible for SUMO
maturation (Kim and Beak, 2009; Hickey et al., 2012).
Some of the well-known protease families include Ulp1/2 in
yeast and SENPs (SENP13 and SENP58) in mammals
(Huang et al., 2009). Among these examples, SENP8 possesses nonspecificity to SUMO and has been identified as a
specific protease for neddylation (Shin et al., 2011).
The C-terminus of Ulp/SENP contains different catalytic
domains, whereas N-terminal sequence frequently dictates
their subcellular localization as the N-terminus-truncated
mutants of SENP3 exhibit similar proteolytic activity to wildtype enzymes, (Nishida et al., 2001). A list of various deSUMOylating enzymes and their properties are summarized
in Table 1. Most SENPs tend to localize in the nucleus or
colocalize in distinguishable subnuclear compartments (Kolli
et al., 2010). For example, the closely related SENP1 and
SENP2 reside in the nuclear envelope by linking the nuclear

Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Huazhong
Agricultural University, Wuhan, China.

HUANG ET AL.

Table 1. Properties of DeSUMOylation Proteases

Name

mRNA
variants

Ulp1
Ulp2
SENP1

1
1
2

SENP2

SENP3

SENP5

SENP6
SENP7
DESI-1

1
1
1

DESI-2
USPL1

1
1

Sublocalization
Nuclear pole
Nucleoplasm
Nuclear pole
Nuclear foci
Nuclear pole
Nuclear foci
Cytoplasm
Nucleolus
Nucleoplasm
Nucleolus
Mitochondria
Nucleoplasm
Nucleoplasm
Nucleus
Cytoplasm
Cytoplasm
Cajal bodies

SUMO isoform
preference

SUMO
polychain
editing

Hydrolase
activity

Isopeptidase
activity

Yes
No
Yes

Yes
Yes
Yes

Smt3
Smt3
SUMO1 and SUMO2/3a

No
Yes
Yesb

Yes

Yes

SUMO1 and SUMO2/3a

No

Unknown

Yes

SUMO2/3

No

Yes

Yes

SUMO2/3

No

No
No
Limited

Yes
Yes
Yes

SUMO2/3
SUMO2/3
SUMO1 and SUMO2/3

Yes
Yes
Yes

No
Limited

Unknown
Yes

Unknown
SUMO2/3 > SUMO1

Unknown
Yes

In most cases, SENP1 can efficiently deconjugate both SUMO1 and SUMO2/3 from its targets. Nevertheless, when regarding embryonic
development, SENP1 possesses a robust activity to SUMO1 removal from its targets, while showing a limited activity to remove SUMO2/3
from its targets.
b
SENP1 can remove SUMO1 from the end of the poly-SUMO2/3 chains, therefore editing the SUMO2/3 chain length for subsequential
efficient chain dismantling.
DeSI, deSUMOylating isopeptidase; SNEP, sentrin-specific protease; SUMO, small ubiquitin-like modifier.

pore complex (NPC) (Zhang et al., 2002). Interestingly,

their localization can undergo some shifting during cell
cycle progression or cell stress (Bailey and OHare, 2004;
Huang et al., 2009; Bawa-Khalfe et al., 2010), implicating
that their activities are spatially regulated or may display
divergent roles according to specific subcellular distribution. Indeed, the specific subcellular localization of mammalian SENPs partly contributes to their specificity (Han
et al., 2004). Moreover, SENPs are capable of processing
all SUMOs due to the existence of catalytic discrimination
within the SUMO family (Hay, 2007). SENP1 and SENP2
can efficiently process and remove all three SUMO isoforms from their targets; however, SENP1 has a robust
activity in deconjugating SUMO1-modified proteins during
mouse embryonic development, while exhibiting limited
efficiency in deSUMOylating SUMO-2/3 from its substrates (Sharma et al., 2013). SENP1 can also remove
SUMO-1 from poly-SUMO-2/3 chains, thus it appears to
have a specialized role in dismantling SUMO2/3 chain
length (Sharma et al., 2013).
Besides the aforementioned SENPs, recently, new classes
of deSUMOylase have been identified and characterized.
DeSUMOylating isopeptidase (DeSI) is one of the family
(DeSI1 and DeSI2) that recognizes different sets of substrates, for example, DeSI1 specifically deSUMOylates the
transcriptional repressor, BZEL (GeneID: 72147) (Shin
et al., 2012). USPL1 is another newly derived protease that
is uniquely localized in glial bodies within the nucleus,
implying a potential role in cell division apart from its
catalytic functions (Schulz et al., 2012).

SENPs and gene expression regulation

Protein deSUMOylation is performed by SUMO proteases and any deactivation in them usually results in the accumulation of SUMOylated proteins in cells. Other than that
SUMO proteases are also involved in numerous biological
processes, including gene transcription, nucleocytoplasmic
transport, cell proliferation, and early embryogenesis (Lu
et al., 2009; Yeh, 2009). A list of substrates of individual
SENPs and their intracellular implications are shown in Table
2. Despite the underlying molecular mechanisms of SENP
functions remains enigmatic, SENP knockout or mutated
mice are embryonically lethal, implicating that the role of
SENPs is not redundant (Yamaguchi et al., 2005; Chiu et al.,
2008; Kang et al., 2010).
Multiple regulators involved in transcriptional repression
are targets for SUMOylation (Lindberg et al., 2010; Witty
et al., 2010). SENPs positively regulate transcriptional activity of targets probably owing to counteraction of the canonical activity of SUMOylation or the maturation of
SUMO precursors during transcriptional repression (Lyst
and Stancheva, 2007). One classical role of SENP1 is its
participation in maintaining the dynamic balance of Elk-1
SUMOylation. Depletion of SENP1 dampens transcriptional
activation of Elk1 and enhances the activation of Wnt target
genes by accumulating SUMOylated TBL1-TBLR1 (Kaikkonen et al., 2010; Choi et al., 2011). A recent study reveals
that SENP1 can regulate mitochondrial biogenesis and
functions through deSUMOylation of PGC-1a and subsequently promote its transcriptional activity (Yu et al., 2012).

DESUMOYLATION IN DISEASE THERAPEUTIC AND PROTEIN REGULATION

Table 2. Improtant Substrates and Intracellular Roles of SENPs

Ligase

Substrate

SENP1

Elk1, HDAC1, Tbl1/TblR1,

HIPK2, MTA1, PGF-1a

SENP2

MEF2A, ERK5, Pc2/CBX, P53

SENP3

MEF2D, EP300, RbBP5, NPM1,

PELP1, LAS1, Mdm2, Borealin

SENP5

Drp1, TGFb1

SENP6

FoxM1, CENPI, RPA1

SENP7

c-Myc

SENP8a

p53, Cul, RPL11, E2F1

Intracellular roles
SENP1 functions as an essential regulator of Elk and Wnt target gene
expression. SENP1 might play a role in mitochondrial dynamics by
balancing SUMOylation of PGC-1a. SENP1 is also required for chromosome cohesion maintenance to prevent aneuploidy (Era et al., 2012).
SENP2 depletion causes a higher SUMOylation level of Pc2/CBX4,
which ultimately leads to transcriptional repression of Gata4 and
Gata6 that are required for embryonic development. Overexpression
of SENP2 in mouse oocytes disrupts spindle assembly, which is
crucial for oocyte maturation and faithful chromosome segregation.
SENP2 regulates P53 stability by modulating SUMOylation status of
Mdm2, an ubiquitin E3 ligase that mediates ubiquitinproteasome
degradation of targets.
Releases SUMO2 from MEF2D to increases its transcriptional activation capability. Serves as a redox sensor, when redistributed into
nucleoplasm upon oxidative stress, to enhance HIF1A transcriptional
activity by deSUMOylating EP300. Regulates the DLX3 gene
expression by deconjugation of SUMO2/3 from RbBP5, which is a
component of SET1/MLL complex. Required for rRNA processing
through deconjugating SUMO2/3 from target proteins, including
NPM1, PELP1, and LAS1. SENP3 also potentiates cell survival by
deSUMOylating Drp1 and thus might be involved in mitochondrial
dynamics. Stabilizes P53 by translocating Mdm2 to the nucleolus,
which is independent of its SUMO protease activity. Removes
SUMO2/3 from Borealin (a component of chromosome passenger
complex [CPC] complex) and regulates its abundance together with
RanBP2, an SUMO E3 ligase.
Translocates from nucleoli to mitochondria during mitosis and, when
depleted, results in altered mitochondrial morphology and metabolism
by losing the activity to SUMO1 proteolysis from mitochondrial
DRP1, which mediated mitochondrial fission. Downregulates the
level of TGFb1 through its deSUMOylation activity. SENP5 is also
required for cell division (Di Bacco et al., 2006)
DeSUMOylates SUMO1 from FoxM1, resulting in transcriptional
activation (Song et al., 2015). Involved in chromosome alignment and
spindle assembly through regulation of the kinetochore CENPHCENPI-CENPK complex, thoroughly protecting CENPI from ubiquitin ligase RNF4-mediated proteasomal degradation (Mukhopadhyay et al., 2010). Deconjugates RPA1 also to prevent recruiting
RAD51 to the DNA damage foci to initiate DNA repair (Dou et al.,
2010). SENP6 is also involved in toll-like receptor (TLR) inflammatory signaling (Liu et al., 2013).
Modulates the stability of c-Myc by balancing the cross talk between
SUMOylation and ubiquitination-mediated degradation of polySUMOylated target (Gonzalez-Prieto et al., 2015).
Regulates the stability of p53 and RPL11 through deconjugating
NEDD8 from the targets (Lv et al., 2014). Plays a role in
inflammatory response by regulating neddylation of Cul (Ehrentraut
et al., 2013). Is involved in regulating transactivation activity of E2F1
to induce apoptosis (Aoki et al., 2013).

a
Strictly speaking, SENP8 is a specific protease for neddylation, not for SUMOylation. However, it possesses SUMO protease activity
after a slight editing in protein sequence.
MEF2, myocyte-specific enhancer factor-2.

Myocyte-specific enhancer factor-2 (MEF2) is a subset of

transcriptional factors that play essential roles in embryonic
development (Lu et al., 2013), and SENP2 is characterized
as a major dominator for MEF2A transcriptional activity as
it directly removes SUMO from the conjugated form and
subsequently boosts its transcriptional activity (Qi et al.,
2014). Similar mechanism is also shown by SENP2 in the
regulation of ERK5 activity in endothelial cells (Heo et al.,
2013).

With the exception to directly dictate gene expression,

some SENPs exert indirect roles by affecting DNA epigenetic modification. One case is SENP2, which regulates
Gata4 and Gata6 transcription through altering the interaction of Pc2/CBX4 on its promoters. In SENP2-deficient
embryo, a higher SUMOylation level of Pc2/CBX4 markedly elevates the level of Pc2/CBX4 on PcG target gene
promoters and boosts methylation of H3K27me3, resulting
in Gata4 and Gata6 transcription repression and consequently

embryonic lethality (Zhang et al., 2004; Kang et al., 2010).

Similarly, SENP3 can deSUMOylate RbBP5 (Nayak et al.,
2014), a component of the SET1/MLL regulatory module,
which additionally comprises WDR5, Ash2L, and DPY-30
(Zhang et al., 2013). SENP3 depletion attenuates deposition of
Ash2L on the DLX3 gene and compromises subsequent H3K4
methylation by SET1/MLL, leading to DLX3 transcription
suppression (Nayak et al., 2014). Based on these evidences,
further studies on other SENPs presumably reveal their nonredundant roles in epigenetic modification.
P53 is a well-known tumor suppressor, which plays an
essential role in preventing aneuploidy by triggering checkpoints that handle the damages or induce apoptosis to eliminate the affected cells (Sherr et al., 2005; Andreou and
Tavernarakis, 2010). Cumulative works discovered pivotal
implications of SENPs on the regulation of p53 activities. The
paramount elucidated case is the SENP2-Mdm2-p53 pathway
(Fig. 1), which modulates p53/Mdm2 circuit in mice trophoblast layer development (Chiu et al., 2008). The full-length
isoform of SENP2 is indispensable and sufficient to negatively
regulate p53 activity; however, when ablated, it apparently
perturbs SUMO modification and subcellular distribution of
Mdm2 by diminishing the target p53 degradation. Interest-

HUANG ET AL.

ingly, reintroduction of SENP2 alleviates this deficiency by

deconjugating SUMOylated Mdm2, thereby decreasing the
p53 level ( Jiang et al., 2011; Heo et al., 2013). Notably, the
nucleolar SUMO-specific protease, SMT3IP1/SENP3, also
participates in the Mdm2-p53 pathway. Overexpression of
SENP3 initiates accumulation of Mdm2 in the nucleolus
and stabilizes p53 protein by competing with p53 for Mdm2
binding, thereby suppressing Mdm2-mediated ubiquitin
proteasome degradation of p53. It is noteworthy that the role
of SENP3 in the facilitation of p53 stabilization is independent
of its deSUMOylation activity (Nishida and Yamada, 2011).
SENPs and ribosome biogenesis

Another charming role of SENPs is evidenced by its participation in ribosomal biogenesis. Eukaryotic ribosome maturation is a tightly coordinated multistep process (Zemp and
Kutay, 2007; Thomson et al., 2013). Intensive evidence from
in vitro investigation of SENP3 in mitosis cells acknowledges
deSUMOylation as a pivotal regulatory process in coordinating
ribosome formation in time with the physiological state of cells.
NPM1/B23 is a plethora of shuttling phosphoproteins,
which associates with 60S preribosome and plays an

FIG. 1. The functions of sentrin-specific protease (SENP)2 and SENP3 in P53 transcription regulation during the Mdm2P53 ubiquitinproteasomal degradation pathway. (A) Under physiological conditions, Mdm-2 itself functions as an ubiquitin ligase E3 toward p53 and, when SUMOylated, it can interact with P53 following the nuclear export of p53, which
entitles P53 to be degraded by 26S proteasome-mediated proteolysis. (B) SENP2 overexpression leads to the deconjugation
of small ubiquitin-like modifier (SUMO) isoform(s) from Mdm-2, which attenuates the association of Mdm-2 and P53 and
abrogates the Mdm-2-mediated P53 degradation. Both of them contribute to the stabilization of P53 and subsequential
transcription of P53 target genes. (C) When compared with SENP2, SENP3 stabilizes P53 through a competitive inhibition
and deSUMOylation activity independent mechanism. SENP3 can restrict Mdm-2 into the nucleolus and has the ability of
competing with P53 for Mdm-2 binding, which prevents Mdm-2-mediated ubiquitinproteasomal degradation of P53. Color
images available online at www.liebertpub.com/dna

DESUMOYLATION IN DISEASE THERAPEUTIC AND PROTEIN REGULATION

important role in the 28S rRNA maturation process (Haindl

et al., 2008; Maggi et al., 2008). Given the crucial role of
NPM1, there exist two conflicting reports. Both studies
confirmed a concise effect of SENP3 and SENP5 on 60S
periribosome maturation and export. One study concludes
that SENP3 and SENP5 are necessary for efficient rRNA
processing through their proteolytic purpose of disengaging
the SUMO isoform from its molecular chaperone, NPM1.
Depletion of SENP3 leads to constitutive SUMOylation of
NPM1, which severely impinges nucleolar ribosomal RNA
processing coupled with accumulation of 32S pre-rRNA
particles, suggesting a defect in splicing the internal transcribed spacer-2 (ITS-2), which resides between 5.8S and
28S. More importantly, SENP5 affects rRNA processing as
well and, when depleted, decreases the production of primary 47S rRNA transcripts (Haindl et al., 2008; Burger,
2013). The second study illustrates that B23/nucleophosmin
forms a complex with SENP3 and SENP5, and depletion of
B23/nucleophosmin conspicuously diminishes the level of
both SENPs. This indicates that the function of SENP3 and
SENP5 in ribosome biogenesis is conferred by physical interaction with B23/nucleophosmin, which entitled B23/NPM1
to regulate their abundance and spectrum of SUMOylated
conjugates within nucleoli (Yun et al., 2008). These results
implicate that although both SENP3 and SENP5 colocalize
with granular components of the nucleolus, they are presumably responsible for deSUMOylation of a specific group
of species, which are crucial for any particular process in the
ribosome biogenesis pathway.
The mechanism of SENP3 involved in ribosome maturation has been explored owing to the identification of a
protein complex comprising PELP1-TEX10-WDR18 in
mammals. It interacts with NPM1, indispensable for 28S
rRNA formation and nucleoplasmic export of 60S ribosomal
intermediates (Finkbeiner et al., 2011). PELP1 is preferentially modified by SUMO2/3 and this modification is reversed by SENP3. Similarly, SENP3 knockdown relocalizes
the expression of PELP1 from the nucleolus to the nucleoplasm (Nair et al., 2010). In SENP3 deficiency cells, the 60S
preribosome subunit retains in the nucleolus, suggesting that
SENP3-mediated removal of SUMO2/3 from the PELP1
complex determines its subnuclear distribution. However, a
SUMOylation-deficient mutant of PELP1 still exports from
the nucleolus upon SENP3 depletion, indicating that PELP1
is not the only target of SENP3 during this process (Finkbeiner et al., 2011). We hypothesize that the coordinated
SUMOylation of several components of the PELP1 complex
emerges as a checkpoint that hinders premature assembly of
the PELP1-WDR18-TEX10 complex to 60S rRNA or serves
as a signal for its release from these structures.
Another prominent example is LAS1L, a nucleolar protein that is essential for cell proliferation, 60S ribosomal
subunit synthesis, and 28S rRNA maturation (Castle et al.,
2010). The loss of LAS1L-associated complex leads to increased abundance of the 32S pre-rRNA subunit. LAS1L
also couples with SENP3, PELP1, TEX10, NOL9, and
WDR18 and cosediments with the pre-60S ribosomal particle. Further studies reveal that SUMOylation of LAS1L is
dictated by SENP3 and either SENP3 or NPM1 depletion
boosts LAS1L SUMOylation and its relocalization from the
nucleolus to the nucleoplasm (Castle et al., 2011). This indicates that SENP3 is partially involved in ribosome bio-

genesis by governing sublocalization of LAS1L, PELP1,

and SENP3 and probably serves as a checkpoint to restrict
the accessibility of SUMO conjugates to 60S.
One landmark step during ribosome biogenesis is preribosome export through nuclear pores. Previous studies
reveal that ribosomal export is an energy-dependent process,
which utilizes the export factor Crm1 and RanGTPase system, and depletion of any of these factors results in rRNA
accumulation within the nucleus (Johnson et al., 2002;
Fromont-Racine et al., 2003). Despite the unequivocal significance of Crm1p to ribosome nuclear export, we can still
envisage that a single export receptor is insufficient to
translocate large assembled cargo through NPC. Nucleophosmin (NPM1) contains a functional Crm1-dependent
nuclear export signal that enables its nucleocytoplasmic
shuttling; furthermore, NPM1 is spatiotemporally controlled
by the Ran-Crm1 complex, suggesting that it might contribute to presubunit export (Wang et al., 2005). Indeed, pre60S export is definitely disturbed after overexpression of
either mutants of nonshuttling NPM1 (Yu et al., 2006). Both
SENP1 and SENP2 display their role in NPC localization,
proper configuration, and function in the maintenance of
nucleoporin homeostasis (Chow et al., 2014), thereby we
could not preclude the possibility that SENP1 and SENP2
are potent factors in ensuring ribosome maturation.
Besides preribosomal export, the involvement of SENPs
in other ribosome biogenesis processes during ribosome
biogenesis is categorically necessary for functional ribosome maturation. It is reported that overexpression of
SENP8 destabilizes a subset of ribosomal proteins and reduces the level of ribosomal protein L11, possibly by coregulating ubiquitinproteasomal degradation, implying that
SENP8-mediated neddylation is related to ribosome biogenesis (Xirodimas et al., 2008). Attractive avenues of future research on the possible link between SUMOylation
and ribosome biogenesis will be to identify unknown
SUMOylation substrates involved in ribosomal maturation,
which will elucidate the potential cross talk of SUMO and
other ubiquitin-related modifiers. This will also improve our
current understanding of whether and how the molecular
pathways that affect ribosome maturation are interrelated.
SENPs and mitochondrial dynamics

The mitochondrion, a multifunctional organelle that can

dynamically undergo fusion and fragmentation to coordinate
cell cycle progression, exerts crucial roles in numerous
cellular processes, including energy metabolism, apoptosis,
and senescence (Lee et al., 2014). It is pertinent to state that
mitochondrial dysfunction has been determined as a vital
contributor to various human diseases (Knott et al., 2008;
Guo et al., 2013). Thus, the regulation of mitochondrial
dynamics during mitosis might be a determinant of cellular
survival, particularly in oocytes, of which developmental
competence is substantially dependent on energy metabolism (Zeng et al., 2014). Despite the functional relevance of
mitochondrial dynamics that has been recognized under the
condition of mitochondria-dependent apoptotic cell death
(Karbowski and Youle, 2003), the regulatory machinery of
mitochondrial remodeling is far less fully understood. Recently, researchers are focused on the possible role of SUMOylation in diagnosis of different diseases and their

therapeutics. Several elegant discoveries are made in the

connection between SUMOylation and mitochondrial morphology regulation.
Drp1, a dynamin-related fission GTPase that is important
for mitochondrial fission, can be SUMOylated, which is
required for Drp1 recruitment to the mitochondrial membrane
(Zunino et al., 2007; Guo et al., 2013); SENP5, a primarily
nucleoli localized SUMO protease with substantial residues
within the cytosol, can translocate from nucleoli to the mitochondrial surface to facilitate deSUMOylation of Drp1 and
alter mitochondrial morphology at G2/M transition (Zunino
et al., 2009). Upon silencing of SENP5, the cell cycle is
significantly compromised. Furthermore, SENP5 overexpression can alleviate SUMOylation-mediated mitochondrial
fragmentation through deconjugation of SUMO-1 from Drp1,
while SENP5 depletion turns mitochondrial morphology
fragmented. Additionally, SENP5 downregulation leads to a
dramatical increase in reactive oxygen species (ROS) production, which can be attenuated by silencing of endogenous
Drp1. All these data reveal SUMOylation as well as SENP5mediated deSUMOylation both as master regulators of mitochondrial metabolism and subsequent cell cycle progression.
Besides SENP5, SENP3 is recently shown to be a regulatory switch for Drp1 through modulating SUMO-2/3 removal
from Drp1, which promotes mitochondrial fragmentation,
releases cytochrome c, and apoptosis that represents a classical example of therapeutic targets (Guo et al., 2013). Similarly, the model for ischemic resistance is classically
reviewed by Anderson and Blackstone (2013). Of note, Drp1
can be SUMOylated by both SUMO-1 and SUMO-2/3, in
which future work is concentrated on characterizing additional mitochondrial SUMO targets and other SUMO proteases involved in mitochondrial morphology that might
provide more insights into the functional link between mitochondrial dynamics and cell cycle progression. All of these
efforts will definitely promote the identification of a new
therapeutic target related to mitochondrial dysfunction.
SENPs and cell cycle regulation

With regard to cell cycle progression, SENP3 is reported

to balance SUMOylation of Borealin couple with RanBP2
(Klein et al., 2009). Borealin is essential for a number of
biological processes, including chromosome segregation,
spindle assembly checkpoint, and cytokinesis (Welburn
et al., 2010; Meyer et al., 2013). Our laboratory is currently
concentrating on different roles of SENP3. We recently
explored nucleolus periphery localization of SENP3 in
mouse oocytes and found that SENP3 depletion exacerbated
the aberrant spindle formation and disrupted meiosis progression, implying a potent role of SENP3 in different reproductive defects (unpublished data). In case of HIF1, an
important transcriptional factor in hypoxia, SENP3 has been
reported to have biphasic redox sensing, resulting in variable SUMOylation of its substrate, p300, which ultimately
deactivates HIF1 (Wang et al., 2012). This study indicated
its important roles in ROS generation, carcinogenesis, and
its cure. Significantly, apart from SENP3, almost all other
SUMO proteases could interfere with the cell cycle to some
extent (Wang et al., 2010; Wang et al., 2013), although the
molecular mechanisms of some of them are not fully known
(Table 2). Based on these studies, deSUMOylation agents

HUANG ET AL.

could be potential therapeutic targets against important ischemic and cancerous diseases. The attempts to make inhibitors to control deSUMOylation are in progress, but no
pharmacological agents are available to date.
Conclusion

The role of SENPs in several important conditions (ischemia), diseases (e.g., Alzheimers disease), anticancer
properties, and regulation of different reproductive disorders is now well established. Several laboratories are
working to develop therapeutic agents, which could alleviate disease conditions. This therapeutic is proposed to
have a pharmacologic agent, which has deSUMOylation
inhibitor activity (Chen et al., 2012). As aforementioned,
SENP3 and SENP5 both localize in the nucleolus and are
integral to ribosome biogenesis and mitochondrial dynamics; moreover, contemporary researchers have verified
links between ribosome biogenesis and carcinogenesis, and
dysfunction of ribosome biogenesis induces P53 activation
(Chan et al., 2011; Burger, 2013; Golomb et al., 2014).
Thus, interference with ribosome biogenesis and mitochondrial metabolism is a potent therapeutic strategy to
suppress carcinogenesis (Sasaki et al., 2011; Andrews
et al., 2013; Quin et al., 2014).
The close cross talk between SUMOylation and other
post-translational modifications such as ubiquitination and
the intricate balance, if disturbed, results in disease between
SUMOylated and ubiquitinated proteins and has attracted
considerable attention (e.g., SENP6 in Table 2). Adding to
this complexity, silencing of SENPs could result in a global
accumulation or loss of SUMO conjugates under different
circumstances due to its distinct activities to SUMO maturation and deSUMOylation. Encouragingly, in vitro SENP
inhibitors are becoming available, making it a powerful tool
to study the functional relevance of SENPs. The emerging
role of SUMOylation in the loading of miRNAs to exosomes and the recent reports of miRNA and SUMOylation
interaction with SENPs having distinct roles in maturation
as well as deSUMOylation, the disruption of which leads to
defective SUMOylation, make it an exciting area of future
research to develop novel therapeutics. Perhaps, in future,
we will see SENPs as the most important sites for pharmacologic agent development.
Acknowledgments

A recent trend in exploiting deSUMOylation as a therapeutic target has attracted attention around the world scientific community. The recent progress in this field, especially in
ribosomal transcription and mitochondrial regulation, states
the need to review deSUMOylation as a therapeutic target.
The work was supported by National Natural Science
Foundation of China (Grant No. 31071273 and 31171378) and
the Fundamental Research Funds for the Central Universities
(Program No. 2014PY045). The authors would like to thank
Dr. Hasan Riaz (Department of Biosciences, COMSATS Institute of Information Technology, Sahiwal, Punjab, Pakistan)
for his kind help in revising the manuscript.
Disclosure Statement

No competing financial interests exist.

DESUMOYLATION IN DISEASE THERAPEUTIC AND PROTEIN REGULATION

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Address correspondence to:

Li-Jun Huo, PhD
Key Laboratory of Agricultural Animal Genetics
Breeding and Reproduction
College of Animal Science and Technology
Huazhong Agricultural University
Wuhan 430070
China
E-mail: lijunhuo@yahoo.com
Received for publication May 11, 2015; received in revised
form July 30, 2015; accepted July 30, 2015.