MAVS Promotes Inflammasome Activation by Targeting ASC for K63-Linked Ubiquitination via the E3 Ligase TRAF3.
Stringent control of inflammasome signaling pathway is important for maintaining immunological balance, yet the molecular mechanisms responsible for its tight regulation are still poorly understood. In this study, we found that the signaling pathway dependent on mitochondrial antiviral signaling protein (MAVS) was required for the optimal activation of apoptosis-associated specklike ... protein (ASC)-dependent inflammasome. In particular, TNFR-associated factor 3 was found to be a direct E3 ligase for ASC. Ubiquitination of ASC at Lys(174) was critical for speck formation and inflammasome activation. Deficiency in MAVS or TNFR-associated factor 3 impaired ASC ubiquitination and cytosolic aggregates formation, resulting in reduced inflammasome response upon RNA virus infection. This study has identified a previously unrecognized role of MAVS in the regulation of inflammasome signaling and provided molecular insight into the mechanisms by which ubiquitination of ASC controls inflammasome activity through the formation of ASC specks.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Apoptosis Regulatory Proteins, Immunoblotting, Immunoprecipitation, Inflammasomes, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Fluorescence, RNA Interference, Signal Transduction, TNF Receptor-Associated Factor 3, Ubiquitination, Virus Diseases
Adaptor Proteins, Signal Transducing, Animals, Apoptosis Regulatory Proteins, Immunoblotting, Immunoprecipitation, Inflammasomes, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Fluorescence, RNA Interference, Signal Transduction, TNF Receptor-Associated Factor 3, Ubiquitination, Virus Diseases
J. Immunol.
Date: May. 15, 2015
PubMed ID: 25847972
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