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

• DOI: 10.1038/s41422-018-0136-1
• Publication Date: 2019-01-16T08:02:41Z
• Authors: Ming-Ming Hu; Wen-Rui He; Peng Gao; Qing Yang; Ke He; Li-Bo Cao; Shu Li; Yu-Qi Feng; Hong-Bing Shu
• Keywords: Mice, Knockout; 0301 basic medicine; Membrane Glycoproteins; Proto-Oncogene Proteins pp60(c-src); NF-kappa B; Herpes Simplex; Herpesvirus 1, Human; Immunity, Innate; Cell Line; Receptors, G-Protein-Coupled; 3. Good health; Bile Acids and Salts; Mice, Inbred C57BL; Mice; 03 medical and health sciences; HEK293 Cells; Animals; Humans; Phosphorylation; Carrier Proteins; beta-Arrestins

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.