MxA interacts with and is modified by the SUMOylation machinery

Brantis-de-Carvalho, Carlos Eduardo; Maarifi, Ghizlane; Boldrin, Paulo Eduardo Gonçalves; Zanelli, Cleslei Fernando; Nisole, Sébastien; Chelbi-Alix, Mounira K.; Valentini, Sandro Roberto

doi:10.1016/j.yexcr.2014.10.020

Cited by 33 publications

(29 citation statements)

References 61 publications

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“…As such, we analyzed the role of MxA within this system. We have previously shown that MxA is conjugated to SUMO at lysine 48 (17). We demonstrated in the study described in this report that the MxA protein is highly stabilized in cells expressing SUMO1 or SUMO3 and that its depletion in SUMO-expressing cells blocks the anti-VSV effect of SUMO, thus signifying that MxA is a key mediator of SUMOinduced resistance to VSV.…”

Section: Discussionsupporting

confidence: 50%

“…that the MxA oligomerization capacity is important for its interaction with SUMO and Ubc9 (17). Accordingly, monomeric mutant MxA-L612K has a reduced interaction with SUMO and Ubc9 (17).…”

Section: Discussionmentioning

confidence: 96%

“…Accordingly, monomeric mutant MxA-L612K has a reduced interaction with SUMO and Ubc9 (17). Importantly, the MxA-L612K mutant is rapidly degraded in cells compared to wild-type MxA, demonstrating that the selfassembly of the MxA protein is critical for protein stability (24).…”

Section: Discussionmentioning

confidence: 99%

“…Rabbit anti-SUMO2/3 antibodies were from Invitrogen, rabbit anti-phospho-IRF3 (Ser396) antibodies were from Cell Signaling, anti-Ubc9 monoclonal antibody (MAb) was from Abgent, and monoclonal anti-6ϫHis antibody was from Clontech. Rabbit anti-MxA antibodies were from Proteintech or were a gift from S. R. Valentini (UNESP, Araraquara, Brazil) (17), and mouse anti-MxA monoclonal antibody M143 was provided by G. Kochs (Institute of Virology, Freiburg, Germany). The 64G12 monoclonal antibody against the human IFN-␣/␤ receptor (anti-IFNAR1 antibody) was a gift from P. Eid (INSERM UMR1014).…”

Section: Methodsmentioning

confidence: 99%

“…It has been shown that oligomerization has a stabilizing effect on MxA protein (24) and that the MxA oligomerization capacity is important for its interaction with SUMO and Ubc9 (17). There- fore, we tested whether SUMO affects MxA oligomerization.…”

Section: Protective Effect Of Sumo In Vsv-infected Cellsmentioning

confidence: 99%

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MxA Mediates SUMO-Induced Resistance to Vesicular Stomatitis Virus

Maarifi

Hannoun

Geoffroy

et al. 2016

J Virol

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Multiple cellular pathways are regulated by small ubiquitin-like modifier (SUMO) modification, including ubiquitin-mediated proteolysis, signal transduction, innate immunity, and antiviral defense. In the study described in this report, we investigated the effects of SUMO on the replication of two members of the Rhabdoviridae family, vesicular stomatitis virus (VSV) and rabies virus (RABV). We show that stable expression of SUMO in human cells confers resistance to VSV infection in an interferon-independent manner. We demonstrate that SUMO expression did not alter VSV entry but blocked primary mRNA synthesis, leading to a reduction of viral protein synthesis and viral production, thus protecting cells from VSV-induced cell lysis. MxA is known to inhibit VSV primary transcription. Interestingly, we found that the MxA protein was highly stabilized in SUMO-expressing cells. Furthermore, extracts from cells stably expressing SUMO exhibited an increase in MxA oligomers, suggesting that SUMO plays a role in protecting MxA from degradation, thus providing a stable intracellular pool of MxA available to combat invading viruses. Importantly, MxA depletion in SUMO-expressing cells abrogated the anti-VSV effect of SUMO. Furthermore, SUMO expression resulted in interferon-regulatory factor 3 (IRF3) SUMOylation, subsequently decreasing RABV-induced IRF3 phosphorylation and interferon synthesis. As expected, this rendered SUMO-expressing cells more sensitive to RABV infection, even though MxA was stabilized in SUMO-expressing cells, since its expression did not confer resistance to RABV. Our findings demonstrate opposing effects of SUMO expression on two viruses of the same family, intrinsically inhibiting VSV infection through MxA stabilization while enhancing RABV infection by decreasing IFN induction. IMPORTANCEWe report that SUMO expression reduces interferon synthesis upon RABV or VSV infection. Therefore, SUMO renders cells more sensitive to RABV but unexpectedly renders cells resistant to VSV by blocking primary mRNA synthesis. Unlike the interferon-mediated innate immune response, intrinsic antiviral resistance is mediated by constitutively expressed restriction factors. Among the various anti-VSV restriction factors, only MxA is known to inhibit VSV primary transcription, and we show here that its expression does not alter RABV infection. Interestingly, MxA depletion abolished the inhibition of VSV by SUMO, demonstrating that MxA mediates SUMO-induced intrinsic VSV resistance. Furthermore, MxA oligomerization is known to be critical for its protein stability, and we show that higher levels of oligomers were formed in cells expressing SUMO than in wildtype cells, suggesting that SUMO may play a role in protecting MxA from degradation, providing a stable intracellular pool of MxA able to protect cells from viral infection. In addition to ubiquitin, several ubiquitin-like (UBL) proteins have been reported to function as protein modifiers that regulate various cellular functions (1). The best-characterized member...

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Section: Discussionsupporting

confidence: 50%

“…that the MxA oligomerization capacity is important for its interaction with SUMO and Ubc9 (17). Accordingly, monomeric mutant MxA-L612K has a reduced interaction with SUMO and Ubc9 (17).…”

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Protective Effect Of Sumo In Vsv-infected Cellsmentioning

confidence: 99%

See 3 more Smart Citations

MxA Mediates SUMO-Induced Resistance to Vesicular Stomatitis Virus

Maarifi

Hannoun

Geoffroy

et al. 2016

J Virol

Self Cite

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Psd3

Tamaddon-Jahromi

Kanamarlapudi

2017

Encyclopedia of Signaling Molecules

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SUMO and Cytoplasmic RNA Viruses: From Enemies to Best Friends

Motiam

Vidal

Seoane

et al. 2020

Advances in Experimental Medicine and Biology

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SUMO is a ubiquitin-like protein that covalently binds to lysine residues of target proteins and regulates many biological processes such as protein subcellular localization or stability, transcription, DNA repair, innate immunity, or antiviral defense. SUMO has a critical role in the signaling pathway governing type I interferon (IFN) production, and among the SUMOylation substrates are many IFN-induced proteins. The overall effect of IFN is increasing global SUMOylation, pointing to SUMO as part of the antiviral stress response. Viral agents have developed different mechanisms to counteract the antiviral activities exerted by SUMO, and some viruses have evolved to exploit the host SUMOylation machinery to modify their own proteins. The exploitation of SUMO has been mainly linked to nuclear replicating viruses due to the predominant nuclear localization of SUMO proteins and enzymes involved in SUMOylation. However, SUMOylation of numerous viral proteins encoded by RNA viruses replicating at the cytoplasm has been lately described. Whether nuclear localization of these viral proteins is required for their SUMOylation is unclear. Here, we summarize the studies on exploitation of SUMOylation by cytoplasmic RNA viruses and discuss about the requirement for nuclear localization of their proteins. Keywords SUMO · RNA viruses · Interferon SUMO ConjugationSUMOylation consists in the covalent attachment of the small ubiquitin-like modifier (SUMO) proteins to specific lysine residues of a target protein. This conjugation is an enzymatic process that occurs in cascade. The precursor SUMO proteins are proteolytically processed to the

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MxA interacts with and is modified by the SUMOylation machinery

Cited by 33 publications

References 61 publications

MxA Mediates SUMO-Induced Resistance to Vesicular Stomatitis Virus

MxA Mediates SUMO-Induced Resistance to Vesicular Stomatitis Virus

Psd3

SUMO and Cytoplasmic RNA Viruses: From Enemies to Best Friends

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