2. Academic Validation
  3. Distinct changes in endosomal composition promote NLRP3 inflammasome activation

Distinct changes in endosomal composition promote NLRP3 inflammasome activation

  • Nat Immunol. 2022 Nov 28. doi: 10.1038/s41590-022-01355-3.
Zhirong Zhang # 1 2 3 4,  Rossella Venditti # 5 6,  Li Ran 7 8 9 10,  Zengzhen Liu 7 8 9 10,  Karl Vivot 7 8 9 10,  Annette Schürmann 11,  Juan S Bonifacino 12,  Maria Antonietta De Matteis 13 14,  Romeo Ricci 15 16 17 18 19
Affiliations

Affiliations

  • 1 Institut de génétique et de biologie moléculaire et cellulaire, Illkirch, France. [email protected].
  • 2 Centre national de la recherche scientifique, UMR7104, Illkirch, France. [email protected].
  • 3 Institut national de la santé et de la recherche médicale, U964, Illkirch, France. [email protected].
  • 4 Université de Strasbourg, Illkirch, France. [email protected].
  • 5 Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
  • 6 Department of Molecular Medicine and Medical Biotechnology, University of Napoli Federico II, Medical School, Naples, Italy.
  • 7 Institut de génétique et de biologie moléculaire et cellulaire, Illkirch, France.
  • 8 Centre national de la recherche scientifique, UMR7104, Illkirch, France.
  • 9 Institut national de la santé et de la recherche médicale, U964, Illkirch, France.
  • 10 Université de Strasbourg, Illkirch, France.
  • 11 Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
  • 12 Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • 13 Telethon Institute of Genetics and Medicine, Pozzuoli, Italy. [email protected].
  • 14 Department of Molecular Medicine and Medical Biotechnology, University of Napoli Federico II, Medical School, Naples, Italy. [email protected].
  • 15 Institut de génétique et de biologie moléculaire et cellulaire, Illkirch, France. [email protected].
  • 16 Centre national de la recherche scientifique, UMR7104, Illkirch, France. [email protected].
  • 17 Institut national de la santé et de la recherche médicale, U964, Illkirch, France. [email protected].
  • 18 Université de Strasbourg, Illkirch, France. [email protected].
  • 19 Laboratoire de biochimie et de biologie moléculaire, Nouvel Hôpital Civil, Strasbourg, France. [email protected].
  • # Contributed equally.
PMID: 36443515 DOI: 10.1038/s41590-022-01355-3
Abstract

Inflammasome complexes are pivotal in the innate immune response. The NLR family pyrin domain containing protein 3 (NLRP3) inflammasome is activated in response to a broad variety of cellular stressors. However, a primary and converging sensing mechanism by the NLRP3 receptor initiating inflammasome assembly remains ill defined. Here, we demonstrate that NLRP3 inflammasome activators primarily converge on disruption of endoplasmic reticulum-endosome membrane contact sites (EECS). This defect causes endosomal accumulation of phosphatidylinositol 4-phosphate (PI4P) and a consequent impairment of endosome-to-trans-Golgi network trafficking (ETT), necessary steps for endosomal recruitment of NLRP3 and subsequent inflammasome activation. Lowering endosomal PI4P levels prevents endosomal association of NLRP3 and inhibits inflammasome activation. Disruption of EECS or ETT is sufficient to enhance endosomal PI4P levels, to recruit NLRP3 to endosomes and to potentiate NLRP3 inflammasome activation. Mice with defects in ETT in the myeloid compartment are more susceptible to lipopolysaccharide-induced sepsis. Our study thus identifies a distinct cellular mechanism leading to endosomal NLRP3 recruitment and inflammasome activation.

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