2. Academic Validation
  3. Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome

Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome

  • Cell. 2021 Nov 11;184(23):5759-5774.e20. doi: 10.1016/j.cell.2021.09.032.
Chen Shen 1,  Runzhi Li 2,  Roberto Negro 3,  Jiewei Cheng 2,  Setu M Vora 1,  Tian-Min Fu 4,  Anmin Wang 2,  Kaixin He 2,  Liudmila Andreeva 1,  Pu Gao 5,  Zhigang Tian 2,  Richard A Flavell 6,  Shu Zhu 7,  Hao Wu 8
Affiliations

Affiliations

  • 1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • 2 Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Institute of Immunology, University of Science and Technology of China, Hefei, China.
  • 3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Castellana Grotte, Bari 70013, Italy.
  • 4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
  • 5 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 6 Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA; Howard Hughes Medical Institute, New Haven, CT, USA.
  • 7 Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Institute of Immunology, University of Science and Technology of China, Hefei, China. Electronic address: [email protected].
  • 8 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 34678144 DOI: 10.1016/j.cell.2021.09.032
Abstract

NLRP6 is important in host defense by inducing functional outcomes including inflammasome activation and interferon production. Here, we show that NLRP6 undergoes liquid-liquid phase separation (LLPS) upon interaction with double-stranded RNA (dsRNA) in vitro and in cells, and an intrinsically disordered poly-lysine sequence (K350-354) of NLRP6 is important for multivalent interactions, phase separation, and inflammasome activation. Nlrp6-deficient or Nlrp6K350-354A mutant mice show reduced inflammasome activation upon mouse hepatitis virus or rotavirus Infection, and in steady state stimulated by intestinal microbiota, implicating NLRP6 LLPS in anti-microbial immunity. Recruitment of ASC via helical assembly solidifies NLRP6 condensates, and ASC further recruits and activates Caspase-1. Lipoteichoic acid, a known NLRP6 ligand, also promotes NLRP6 LLPS, and DHX15, a helicase in NLRP6-induced interferon signaling, co-forms condensates with NLRP6 and dsRNA. Thus, LLPS of NLRP6 is a common response to ligand stimulation, which serves to direct NLRP6 to distinct functional outcomes depending on the cellular context.

Keywords

IDRs; LLPS; MHV; NLRP6; RV; dsRNA; inflammasome; liquid-liquid phase separation.

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