TRIM41 is required to innate antiviral response by polyubiquitinating BCL10 and recruiting NEMO

Signal Transduct Target Ther. 2021 Feb 28;6(1):90. doi: 10.1038/s41392-021-00477-8.

Abstract

Sensing of pathogenic nucleic acids by pattern recognition receptors (PRR) not only initiates anti-microbe defense but causes inflammatory and autoimmune diseases. E3 ubiquitin ligase(s) critical in innate response need to be further identified. Here we report that the tripartite motif-containing E3 ubiquitin ligase TRIM41 is required to innate antiviral response through facilitating pathogenic nucleic acids-triggered signaling pathway. TRIM41 deficiency impairs the production of inflammatory cytokines and type I interferons in macrophages after transfection with nucleic acid-mimics and infection with both DNA and RNA viruses. In vivo, TRIM41 deficiency leads to impaired innate response against viruses. Mechanistically, TRIM41 directly interacts with BCL10 (B cell lymphoma 10), a core component of CARD proteins-BCL10 - MALT1 (CBM) complex, and modifies the Lys63-linked polyubiquitylation of BCL10, which, in turn, hubs NEMO for activation of NF-κB and TANK-binding kinase 1 (TBK1) - interferon regulatory factor 3 (IRF3) pathways. Our study suggests that TRIM41 is the potential universal E3 ubiquitin ligase responsible for Lys63 linkage of BCL10 during innate antiviral response, adding new insight into the molecular mechanism for the control of innate antiviral response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Cell CLL-Lymphoma 10 Protein / genetics*
  • DNA Viruses / genetics
  • DNA Viruses / pathogenicity
  • Host-Pathogen Interactions / genetics
  • Humans
  • I-kappa B Kinase / genetics*
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology
  • Interferon Regulatory Factor-3 / genetics
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / genetics
  • Nucleic Acids / genetics
  • Nucleic Acids / immunology
  • Protein Serine-Threonine Kinases / genetics
  • RNA Viruses / genetics
  • RNA Viruses / pathogenicity
  • Receptors, Pattern Recognition / genetics
  • Receptors, Pattern Recognition / immunology
  • Ubiquitin-Protein Ligases / genetics*
  • Virus Diseases / genetics*
  • Virus Diseases / immunology
  • Virus Diseases / virology

Substances

  • B-Cell CLL-Lymphoma 10 Protein
  • BCL10 protein, human
  • IKBKG protein, human
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Nucleic Acids
  • Receptors, Pattern Recognition
  • TRIM41 protein, human
  • Ubiquitin-Protein Ligases
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • I-kappa B Kinase
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein