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MAVS Promotes Inflammasome Activation by Targeting ASC for K63-Linked Ubiquitination via the E3 Ligase TRAF3

Kai Guan1, Congwen Wei1, Zirui Zheng1

  • 1State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China;

Journal of Immunology (Baltimore, Md. : 1950)
|April 8, 2015
PubMed

Insights

Mitochondrial antiviral signaling protein (MAVS) and TNFR-associated factor 3 are crucial for optimal inflammasome activation by enabling ASC ubiquitination and speck formation, essential for antiviral immune responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Inflammasome signaling is critical for immune balance, but its regulatory mechanisms remain unclear.
  • The apoptosis-associated specklike protein (ASC)-dependent inflammasome requires precise control for effective immune responses.

Purpose of the Study:

  • To elucidate the molecular mechanisms regulating inflammasome activation.
  • To investigate the role of mitochondrial antiviral signaling protein (MAVS) in inflammasome signaling.
  • To identify key regulators of ASC ubiquitination and inflammasome assembly.

Main Methods:

  • Investigated the requirement of MAVS-dependent signaling for inflammasome activation.
  • Identified TNFR-associated factor 3 as an E3 ligase for ASC.
  • Assessed the impact of MAVS or TNFR-associated factor 3 deficiency on ASC ubiquitination, speck formation, and inflammasome response during RNA virus infection.

Main Results:

  • MAVS signaling is essential for optimal ASC-dependent inflammasome activation.
  • TNFR-associated factor 3 directly ubiquitinates ASC at Lys(174), a critical step for speck formation and inflammasome activation.
  • Deficiency in MAVS or TNFR-associated factor 3 impairs ASC ubiquitination and cytosolic aggregate formation, leading to reduced inflammasome responses to RNA viruses.

Conclusions:

  • MAVS plays a previously unrecognized role in regulating inflammasome signaling.
  • ASC ubiquitination, mediated by TNFR-associated factor 3, is a key mechanism controlling inflammasome activity via ASC speck formation.
  • This study provides molecular insights into the regulation of inflammasome activation and its role in antiviral immunity.

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