USP18 positively regulates innate antiviral immunity by promoting K63-linked polyubiquitination of MAVS

Nat Commun. 2021 May 20;12(1):2970. doi: 10.1038/s41467-021-23219-4.

Abstract

Activation of MAVS, an adaptor molecule in Rig-I-like receptor (RLR) signaling, is indispensable for antiviral immunity, yet the molecular mechanisms modulating MAVS activation are not completely understood. Ubiquitination has a central function in regulating the activity of MAVS. Here, we demonstrate that a mitochondria-localized deubiquitinase USP18 specifically interacts with MAVS, promotes K63-linked polyubiquitination and subsequent aggregation of MAVS. USP18 upregulates the expression and production of type I interferon following infection with Sendai virus (SeV) or Encephalomyocarditis virus (EMCV). Mice with a deficiency of USP18 are more susceptible to RNA virus infection. USP18 functions as a scaffold protein to facilitate the re-localization of TRIM31 and enhances the interaction between TRIM31 and MAVS in mitochondria. Our results indicate that USP18 functions as a post-translational modulator of MAVS-mediated antiviral signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / isolation & purification
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cardiovirus Infections / immunology*
  • Cardiovirus Infections / virology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Encephalomyocarditis virus / immunology
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Immunity, Innate
  • Interferon Type I / metabolism
  • Lysine / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Protein Processing, Post-Translational / immunology
  • RAW 264.7 Cells
  • Recombinant Proteins / genetics
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Respirovirus Infections / immunology*
  • Respirovirus Infections / virology
  • Sendai virus / immunology
  • Signal Transduction / immunology
  • Tripartite Motif Proteins / metabolism
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / isolation & purification
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • IPS-1 protein, mouse
  • Interferon Type I
  • MAVS protein, human
  • Recombinant Proteins
  • Tripartite Motif Proteins
  • TRIM31 protein, human
  • TRIM31 protein, mouse
  • Ubiquitin-Protein Ligases
  • Usp18 protein, mouse
  • USP18 protein, human
  • Ubiquitin Thiolesterase
  • Lysine