2. Academic Validation
  3. MAVS deSUMOylation by SENP1 inhibits its aggregation and antagonizes IRF3 activation

MAVS deSUMOylation by SENP1 inhibits its aggregation and antagonizes IRF3 activation

  • Nat Struct Mol Biol. 2023 May 15. doi: 10.1038/s41594-023-00988-8.
Tong Dai # 1 2 3,  Lei Zhang # 4,  Yu Ran # 3,  Meirong Zhang 2,  Bing Yang 3 5,  Huasong Lu 3,  Shixian Lin 6,  Long Zhang 7,  Fangfang Zhou 8 9
Affiliations

Affiliations

  • 1 Center for Infection & Immunity of International Institutes of Medicine, The Fourth Affiliated Hospital, ZheJiang University School of Medicine, Yiwu, China.
  • 2 Institutes of Biology and Medical Science, Soochow University, Suzhou, China.
  • 3 MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 4 Department of Orthopaedic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 5 Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
  • 6 MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  • 7 MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  • 8 Center for Infection & Immunity of International Institutes of Medicine, The Fourth Affiliated Hospital, ZheJiang University School of Medicine, Yiwu, China. [email protected].
  • 9 Institutes of Biology and Medical Science, Soochow University, Suzhou, China. [email protected].
  • # Contributed equally.
PMID: 37188808 DOI: 10.1038/s41594-023-00988-8
Abstract

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.

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