4.5 Article

MAVS deSUMOylation by SENP1 inhibits its aggregation and antagonizes IRF3 activation

Journal

NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 30, Issue 6, Pages 785-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41594-023-00988-8

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The study reveals that SUMO-specific protease 1 regulates antiviral immunity by deSUMOylating MAVS, which promotes MAVS SUMOylation and aggregation, leading to recruitment and activation of IRF3 for timely antiviral responses. The findings demonstrate the involvement of SUMOylation in MAVS phase separation and reveal a previously unknown mechanism mediated by the SIM in IRF3 for its enrichment in multivalent MAVS droplets.
Mitochondrial antiviral signaling protein (MAVS) is an adapter that recruits and activates IRF3. However, the mechanisms underpinning the interplay between MAVS and IRF3 are largely unknown. Here we show that small ubiquitin-like modifier (SUMO)-specific protease 1 negatively regulates antiviral immunity by deSUMOylating MAVS. Upon virus infection, PIAS3-induced poly-SUMOylation promotes lysine 63-linked poly-ubiquitination and aggregation of MAVS. Notably, we observe that SUMO conjugation is required for MAVS to efficiently produce phase-separated droplets through association with a newly identified SUMO-interacting motif (SIM) in MAVS. We further identify a yet-unknown SIM in IRF3 that mediates its enrichment to the multivalent MAVS droplets. Conversely, IRF3 phosphorylation at crucial residues close to SIM rapidly disables SUMO-SIM interactions and releases activated IRF3 from MAVS. Our findings implicate SUMOylation in MAVS phase separation and suggest a thus far unknown regulatory process by which IRF3 can be efficiently recruited and released to facilitate timely activation of antiviral responses. Here the authors show that PIAS3/SENP1-mediated poly-SUMOylation of MAVS regulates its interaction with IRF3, whose SUMO-interacting motif (SIM) guides binding to SUMOylated MAVS. IRF3 phosphorylation, close to its SIM, dismantles SUMO-dependent aggregates and releases activated IRF3.

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