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Publications

Journal Article Research Support, N.I.H., Extramural Ppublish 32 citations

PubMed: 36604592 DOI: 10.1038/s41556-022-01039-y

OASL phase condensation induces amyloid-like fibrillation of RIPK3 to promote virus-induced necroptosis.

Nat Cell Biol 25(1):92-107

Authors: Shin-Ae Lee, Lin-Chun Chang, WooRam Jung, James W Bowman, Dokyun Kim, Weiqiang Chen, Suan-Sin Foo, Youn Jung Choi, Un Yung Choi, Anna Bowling, Ji-Seung Yoo, Jae U Jung

Affiliations

  • Department of Cancer Biology, Infection Biology Program, and Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Immunology Program of the Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Department of Cancer Biology, Infection Biology Program, and Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Department of Cancer Biology, Infection Biology Program, and Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Center for Study of Emerging and Re-emerging Viruses, Korea Virus Research Institute, Institute for Basic Science, Daejeon, Republic of Korea.
  • Department of Cancer Biology, Infection Biology Program, and Global Center for Pathogen Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Abstract

RIPK3-ZBP1-MLKL-mediated necroptosis is a proinflammatory cell death process that is crucial for antiviral host defence. RIPK3 self-oligomerization and autophosphorylation are prerequisites for executing necroptosis, yet the underlying mechanism of virus-induced RIPK3 activation remains elusive. Interferon-inducible 2'-5' oligoadenylate synthetase-like (OASL) protein is devoid of enzymatic function but displays potent antiviral activity. Here we describe a role of OASL as a virus-induced necroptosis promoter that scaffolds the RIPK3-ZBP1 non-canonical necrosome via liquid-like phase condensation. This liquid-like platform of OASL recruits RIPK3 and ZBP1 via protein-protein interactions to provide spatial segregation for RIPK3 nucleation. This process facilitates the amyloid-like fibril formation and activation of RIPK3 and thereby MLKL phosphorylation for necroptosis. Mice deficient in Oasl1 exhibit severely impaired necroptosis and attenuated inflammation after viral infection, resulting in uncontrolled viral dissemination and lethality. Our study demonstrates an interferon-induced innate response whereby OASL scaffolds RIPK3-ZBP1 assembly via its phase-separated liquid droplets to facilitate necroptosis-mediated antiviral immunity.

MeSH

Amyloid, Infections, Viruses, Cell Biology, 2',5'-Oligoadenylate Synthetase, Necroptosis

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