TRIM32-TAX1BP1-dependent selective autophagic degradation of TRIF negatively regulates TLR3/4-mediated innate immune responses

PLoS Pathog. 2017 Sep 12;13(9):e1006600. doi: 10.1371/journal.ppat.1006600. eCollection 2017 Sep.

Abstract

Toll-like receptor (TLR)-mediated signaling are critical for host defense against pathogen invasion. However, excessive responses would cause harmful damages to the host. Here we show that deficiency of the E3 ubiquitin ligase TRIM32 increases poly(I:C)- and LPS-induced transcription of downstream genes such as type I interferons (IFNs) and proinflammatory cytokines in both primary mouse immune cells and in mice. Trim32-/- mice produced higher levels of serum inflammatory cytokines and were more sensitive to loss of body weight and inflammatory death upon Salmonella typhimurium infection. TRIM32 interacts with and mediates the degradation of TRIF, a critical adaptor protein for TLR3/4, in an E3 activity-independent manner. TRIM32-mediated as well as poly(I:C)- and LPS-induced degradation of TRIF is inhibited by deficiency of TAX1BP1, a receptor for selective autophagy. Furthermore, TRIM32 links TRIF and TAX1BP1 through distinct domains. These findings suggest that TRIM32 negatively regulates TLR3/4-mediated immune responses by targeting TRIF to TAX1BP1-mediated selective autophagic degradation.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Autophagy*
  • Cytokines / metabolism
  • Humans
  • Immunity, Innate* / drug effects
  • Immunity, Innate* / immunology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipopolysaccharides / pharmacology
  • Macrophages / immunology
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Toll-Like Receptor 3 / genetics
  • Toll-Like Receptor 3 / metabolism*
  • Toll-Like Receptor 4 / metabolism*
  • Transcription Factors / metabolism*
  • Tripartite Motif Proteins / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Neoplasm Proteins
  • TAX1BP1 protein, human
  • TICAM1 protein, human
  • TLR3 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Transcription Factors
  • Tripartite Motif Proteins
  • TRIM32 protein, human
  • Ubiquitin-Protein Ligases

Grant support

This work was supported by grants from the Ministry of Science and Technology of China (2016YFA0502100, 2014CB910103), the National Natural Science Foundation of China (31630045, 31521091, and 91429304), and the National Postdoctoral Program for Innovative Talents (BX201600116). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.