title: The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation.
abstract: NLRP3 is a key component of the macromolecular signaling complex called the inflammasome that promotes caspase 1-dependent production of IL-1β. The adaptor ASC is necessary for NLRP3-dependent inflammasome function, but it is not known whether ASC is a sufficient partner and whether inflammasome formation occurs in the cytosol or in association with mitochondria is controversial. Here, we show that the mitochondria-associated adaptor molecule, MAVS, is required for optimal NLRP3 inflammasome activity. MAVS mediates recruitment of NLRP3 to mitochondria, promoting production of IL-1β and the pathophysiologic activity of the NLRP3 inflammasome in vivo. Our data support a more complex model of NLRP3 inflammasome activation than previously appreciated, with at least two adapters required for maximal function. Because MAVS is a mitochondria-associated molecule previously considered to be uniquely involved in type 1 interferon production, these findings also reveal unexpected polygamous involvement of PYD/CARD-domain-containing adapters in innate immune signaling events.
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. subramaniann@niaid.nih.gov
authors.forename: Naeha
authors.initials: N
authors.lastname: Subramanian
authors.forename: Kannan
authors.initials: K
authors.lastname: Natarajan
authors.forename: Menna R
authors.initials: MR
authors.lastname: Clatworthy
authors.forename: Ze
authors.initials: Z
authors.lastname: Wang
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Germain
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D007684:Kidney Tubules / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009336:Necrosis / Q000473:pathology; D054730:Protein Interaction Domains and Motifs; D016415:Sequence Alignment
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; C505371:MAVS protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human