TRIM30α Is a Negative-Feedback Regulator of the Intracellular DNA and DNA Virus-Triggered Response by Targeting STING

PLoS Pathog. 2015 Jun 26;11(6):e1005012. doi: 10.1371/journal.ppat.1005012. eCollection 2015 Jun.

Abstract

Uncontrolled immune responses to intracellular DNA have been shown to induce autoimmune diseases. Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host. Here, we report that the E3 ubiquitin ligase tripartite motif protein 30α (TRIM30α) was induced by herpes simplex virus type 1 (HSV-1) infection in dendritic cells (DCs). Knockdown or genetic ablation of TRIM30α augmented the type I IFNs and interleukin-6 response to intracellular DNA and DNA viruses. Trim30α-deficient mice were more resistant to infection by DNA viruses. Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response. Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway. These findings indicate that E3 ligase TRIM30α is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA / metabolism*
  • DNA Viruses / genetics
  • DNA Viruses / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Immunity, Innate
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Signal Transduction / immunology
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination

Substances

  • DNA-Binding Proteins
  • Membrane Proteins
  • Sting1 protein, mouse
  • Transcription Factors
  • Trim30a protein, mouse
  • DNA
  • Ubiquitin-Protein Ligases

Grants and funding

This work was supported by grants from the national key project of 973 (2013CB530504) and the National Natural Science Foundation of China (31030029, 31230024, 81361120409). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.