The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation

Cell. 2013 Apr 11;153(2):348-61. doi: 10.1016/j.cell.2013.02.054.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Animals
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cytoskeletal Proteins / metabolism
  • Humans
  • Inflammasomes / immunology
  • Inflammasomes / metabolism*
  • Interleukin-1beta / immunology
  • Interleukin-1beta / metabolism
  • Kidney Tubules / pathology
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Molecular Sequence Data
  • Monocytes / immunology
  • Monocytes / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Necrosis / pathology
  • Protein Interaction Domains and Motifs
  • Sequence Alignment

Substances

  • Adaptor Proteins, Signal Transducing
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • PYCARD protein, human
  • VISA protein, human