2. Academic Validation
  3. Virus-induced accumulation of intracellular bile acids activates the TGR5-β-arrestin-SRC axis to enable innate antiviral immunity

Virus-induced accumulation of intracellular bile acids activates the TGR5-β-arrestin-SRC axis to enable innate antiviral immunity

  • Cell Res. 2019 Mar;29(3):193-205. doi: 10.1038/s41422-018-0136-1.
Ming-Ming Hu 1 2 3,  Wen-Rui He 4,  Peng Gao 4,  Qing Yang 4,  Ke He 5,  Li-Bo Cao 6,  Shu Li 7 4,  Yu-Qi Feng 5,  Hong-Bing Shu 8 9
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. mmhu@whu.edu.cn.
  • 2 Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China. mmhu@whu.edu.cn.
  • 3 State Key Laboratory of Virology, Wuhan University, Wuhan, 430072, China. mmhu@whu.edu.cn.
  • 4 Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China.
  • 5 College of Chemistry and Molecular Sciences, Wuhan University, 430072, Wuhan, China.
  • 6 College of Life Sciences, Wuhan University, Wuhan, 430072, China.
  • 7 Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  • 8 Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. shuh@whu.edu.cn.
  • 9 Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China. shuh@whu.edu.cn.
PMID: 30651583 DOI: 10.1038/s41422-018-0136-1
Abstract

The mechanisms on metabolic regulation of immune responses are still elusive. We show here that viral Infection induces immediate-early NF-κB activation independent of viral nucleic acid-triggered signaling, which triggers a rapid transcriptional induction of bile acid (BA) transporter and rate-limiting biosynthesis Enzymes as well as accumulation of intracellular BAs in divergent cell types. The accumulated intracellular BAs activate Src kinase via the TGR5-GRK-β-arrestin axis, which mediates tyrosine phosphorylation of multiple Antiviral signaling components including RIG-I, VISA/MAVS, MITA/STING, TBK1 and IRF3. The tyrosine phosphorylation of these components by Src conditions for efficient innate Antiviral immune response. Consistently, TGR5 deficiency impairs innate Antiviral immunity, whereas BAs exhibit potent Antiviral activity in wild-type but not TGR5-deficient cells and mice. Our findings reveal an intrinsic and universal role of intracellular BA metabolism in innate Antiviral immunity.

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