Expanding SUMO and ubiquitin-mediated signaling through hybrid SUMO-ubiquitin chains and their receptors

Guzzo, Catherine M.; Matunis, Michael J.

doi:10.4161/cc.24332

Cited by 29 publications

(22 citation statements)

References 8 publications

(11 reference statements)

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“…49–52 The SUMO2-3 isoforms perform poly-SUMOylation PTMs and can modulate protein degradation. 53,54 Recent studies suggest that the SUMO2-3 isoforms can also target proteins for poly-ubiquitination and subsequent degradation via the proteasome. 54,55 SUMO4 differs from the other isoforms in that it has proline rather than glutamine at residue 90 and is not processed and conjugated at baseline.…”

Section: Discussionmentioning

confidence: 99%

“…53,54 Recent studies suggest that the SUMO2-3 isoforms can also target proteins for poly-ubiquitination and subsequent degradation via the proteasome. 54,55 SUMO4 differs from the other isoforms in that it has proline rather than glutamine at residue 90 and is not processed and conjugated at baseline. It can, however, be hydrolyzed under certain stress conditions.…”

Section: Discussionmentioning

confidence: 99%

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UBC9-Mediated Sumoylation Favorably Impacts Cardiac Function in Compromised Hearts

Gupta

McLendon

Gulick

et al. 2016

Circulation Research

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Rationale SUMOylation plays an important role in cardiac function and can be protective against cardiac stress. Recent studies show that SUMOylation is an integral part of the ubiquitin proteasome system (UPS) and expression of the SUMO E2 enzyme UBC9 improves cardiac protein quality control. However, the precise role of SUMOylation on other protein degradation pathways, particularly autophagy, remains undefined in the heart. Objective To determine whether SUMOylation affects cardiac autophagy and whether this effect is protective in a mouse model of proteotoxic cardiac stress. Methods and Results We modulated expression of UBC9, a SUMO E2 ligase, using gain- and loss-of-function in neonatal rat ventricular cardiomyocytes (NRVC). UBC9 expression appeared to directly alter autophagic flux. To confirm this effect in vivo, we generated transgenic mice overexpressing UBC9 in cardiomyocytes (CM). These mice have an increased level of SUMOylation at baseline and, in confirmation of the data obtained from NRVCs, demonstrated increased autophagy, suggesting that increased UBC9-mediated SUMOylation is sufficient to upregulate cardiac autophagy. Finally, we tested the protective role of SUMOylation-mediated autophagy by expressing UBC9 in a model of cardiac proteotoxicity, induced by CM-specific expression of a mutant αB crystallin, CryABR120G, which shows impaired autophagy. UBC9 overexpression reduced aggregate formation, decreased fibrosis, reduced hypertrophy and improved cardiac function and survival. Conclusions The data show that increased UBC9-mediated SUMOylation is sufficient to induce relatively high levels of autophagy and may represent a novel strategy for increasing autophagic flux and ameliorating morbidity in proteotoxic cardiac disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

UBC9-Mediated Sumoylation Favorably Impacts Cardiac Function in Compromised Hearts

Gupta

McLendon

Gulick

et al. 2016

Circulation Research

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“…The establishment of hybrid chains at DNA damage sites, through the activity of the SUMO-targeted ubiquitin ligase RNF4, recruits RAP80 and the BRCA1-A complex to DNA lesions (41). In addition, the proteasomal subunit S5a/RPN10, which has protease activity, bears UIM and SIM motifs and it is intriguing to think that this protein could be responsible for the docking of hybrid SUMO-ubiquitin chains at the proteasome (42). …”

Section: Sumo Is Involved In Proteostasis Via Crosstalk With Ubiquitinmentioning

confidence: 99%

Ubiquitin-dependent and independent roles of SUMO in proteostasis

Liebelt

Vertegaal

2016

American Journal of Physiology-Cell Physiology

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Cellular proteomes are continuously undergoing alterations as a result of new production of proteins, protein folding, and degradation of proteins. The proper equilibrium of these processes is known as proteostasis, implying that proteomes are in homeostasis. Stress conditions can affect proteostasis due to the accumulation of misfolded proteins as a result of overloading the degradation machinery. Proteostasis is affected in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and multiple polyglutamine disorders including Huntington's disease. Owing to a lack of proteostasis, neuronal cells build up toxic protein aggregates in these diseases. Here, we review the role of the ubiquitin-like posttranslational modification SUMO in proteostasis. SUMO alone contributes to protein homeostasis by influencing protein signaling or solubility. However, the main contribution of SUMO to proteostasis is the ability to cooperate with, complement, and balance the ubiquitin-proteasome system at multiple levels. We discuss the identification of enzymes involved in the interplay between SUMO and ubiquitin, exploring the complexity of this crosstalk which regulates proteostasis. These enzymes include SUMO-targeted ubiquitin ligases and ubiquitin proteases counteracting these ligases. Additionally, we review the role of SUMO in brain-related diseases, where SUMO is primarily investigated because of its role during formation of aggregates, either independently or in cooperation with ubiquitin. Detailed understanding of the role of SUMO in these diseases could lead to novel treatment options.

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“…In general, the SIMs contain a hydrophobic core (V/I-X-V/I-V/I or V/I-V/I-X-V/I/L) flanked by acidic residues either upstream or downstream (14)(15)(16)(17). In addition to being structurally related, ubiquitin and SUMO modifications of substrates occur preferentially on lysine residues, and ubiquitin can be hybridized with the SUMO moiety by anchoring to the lysine on poly-SUMO (18,19). Cross talk between the two PTMs may be involved in genome stability and cell growth, which are associated with pathogen resistance and cancer treatment (20).…”

mentioning

confidence: 99%

SUMO Modification Stabilizes Enterovirus 71 Polymerase 3D To Facilitate Viral Replication

Liu

Zheng

Shu

et al. 2016

J Virol

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Accumulating evidence suggests that viruses hijack cellular proteins to circumvent the host immune system. Ubiquitination and SUMOylation are extensively studied posttranslational modifications (PTMs) that play critical roles in diverse biological processes. Cross talk between ubiquitination and SUMOylation of both host and viral proteins has been reported to result in distinct functional consequences. Enterovirus 71 (EV71), an RNA virus belonging to the family Picornaviridae, is a common cause of hand, foot, and mouth disease. Little is known concerning how host PTM systems interact with enteroviruses. Here, we demonstrate that the 3D protein, an RNA-dependent RNA polymerase (RdRp) of EV71, is modified by small ubiquitin-like modifier 1 (SUMO-1) both during infection and in vitro. Residues K159 and L150/D151/L152 were responsible for 3D SUMOylation as determined by bioinformatics prediction combined with site-directed mutagenesis. Also, primer-dependent polymerase assays indicated that mutation of SUMOylation sites impaired 3D polymerase activity and virus replication. Moreover, 3D is ubiquitinated in a SUMO-dependent manner, and SUMOylation is crucial for 3D stability, which may be due to the interplay between the two PTMs. Importantly, increasing the level of SUMO-1 in EV71-infected cells augmented the SUMOylation and ubiquitination levels of 3D, leading to enhanced replication of EV71. These results together suggested that SUMO and ubiquitin cooperatively regulated EV71 infection, either by SUMO-ubiquitin hybrid chains or by ubiquitin conjugating to the exposed lysine residue through SUMOylation. Our study provides new insight into how a virus utilizes cellular pathways to facilitate its replication. IMPORTANCEInfection with enterovirus 71 (EV71) often causes neurological diseases in children, and EV71 is responsible for the majority of fatalities. Based on a better understanding of interplay between virus and host cell, antiviral drugs against enteroviruses may be developed. As a dynamic cellular process of posttranslational modification, SUMOylation regulates global cellular protein localization, interaction, stability, and enzymatic activity. However, little is known concerning how SUMOylation directly influences virus replication by targeting viral polymerase. Here, we found that EV71 polymerase 3D was SUMOylated during EV71 infection and in vitro. Moreover, the SUMOylation sites were determined, and in vitro polymerase assays indicated that mutations at SUMOylation sites could impair polymerase synthesis. Importantly, 3D is ubiquitinated in a SUMOylation-dependent manner that enhances the stability of the viral polymerase. Our findings indicate that the two modifications likely cooperatively enhance virus replication. Our study may offer a new therapeutic strategy against virus replication. S mall ubiquitin-like modifier (SUMO) modification, a member of the group of posttranslational modifications (PTMs), is important for the regulation of many cellular proteins and pathways (1). SUMO is a novel...

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Expanding SUMO and ubiquitin-mediated signaling through hybrid SUMO-ubiquitin chains and their receptors

Cited by 29 publications

References 8 publications

UBC9-Mediated Sumoylation Favorably Impacts Cardiac Function in Compromised Hearts

UBC9-Mediated Sumoylation Favorably Impacts Cardiac Function in Compromised Hearts

Ubiquitin-dependent and independent roles of SUMO in proteostasis

SUMO Modification Stabilizes Enterovirus 71 Polymerase 3D To Facilitate Viral Replication

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