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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
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TRIM65-catalized ubiquitination is essential for MDA5-mediated antiviral innate immunity

Xueting Lang1,2,3, Tiantian Tang1, Tengchuan Jin1

  • 1Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.

The Journal of Experimental Medicine
|December 30, 2016
PubMed

Insights

TRIM65 is essential for MDA5 activation in antiviral immunity. It promotes ubiquitination, leading to MDA5 oligomerization and type I interferon production, crucial for fighting viral infections like EMCV.

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • MDA5 functions as a cytoplasmic sensor for double-stranded RNA, initiating antiviral innate immunity via type I interferon signaling.
  • The precise mechanisms governing MDA5 activation remain incompletely understood.

Purpose of the Study:

  • To elucidate the mechanism of MDA5 activation.
  • To identify key regulators involved in MDA5-mediated antiviral responses.

Main Methods:

  • Co-immunoprecipitation assays to identify TRIM65 interaction with MDA5.
  • Site-directed mutagenesis to investigate the role of lysine 743 ubiquitination.
  • Analysis of interferon regulatory factor 3 (IRF3) activation and type I interferon production in Trim65-deficient cells and mice.
  • Encephalomyocarditis virus (EMCV) infection models in wild-type and Trim65 knockout mice.

Main Results:

  • TRIM65 specifically interacts with MDA5 and mediates its K63-linked ubiquitination at lysine 743.
  • This ubiquitination is critical for MDA5 oligomerization and subsequent activation.
  • Trim65 deficiency abrogates MDA5 agonist or EMCV-induced IRF3 activation and type I interferon production.
  • TRIM65 deficiency does not impact RIG-I, TLR3, or cGAS signaling pathways.
  • Trim65 knockout mice exhibit increased susceptibility to EMCV infection and impaired in vivo type I interferon production.

Conclusions:

  • TRIM65 is identified as a crucial component of the MDA5 signaling pathway.
  • Ubiquitination mediated by TRIM65 is essential for MDA5 oligomerization and activation during antiviral innate immunity.
  • This study provides physiological evidence for the role of ubiquitination in MDA5 function.

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