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
复制标题
病毒诱导的细胞内胆汁酸积累激活 TGR5-β-arrestin-SRC 轴，从而实现先天抗病毒免疫
DOI：
10.1038/s41422-018-0136-1
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发表时间：
2019-03-01
期刊：
影响因子：
44.1
通讯作者：
Shu, Hong-Bing
中科院分区：
文献类型：
--
作者：
Hu, Ming-Ming;He, Wen-Rui;Shu, Hong-Bing
免疫反应的代谢调节机制仍然是难以捉摸的。我们在这里表明，病毒感染诱导立即早期NF-κ B B激活独立于病毒核酸触发的信号，这触发了胆汁酸（BA）转运蛋白和限速生物合成酶的快速转录诱导，以及在不同的细胞类型的细胞内BA的积累。积累的细胞内BA通过TGR 5-GRK-beta-arrestin轴激活SRC激酶，其介导多种抗病毒信号传导组分的酪氨酸磷酸化，包括RIG-I、VISA/MAVS、MITA/STING、TBK 1和IRF 3。这些组分的酪氨酸磷酸化通过SRC条件进行有效的先天性抗病毒免疫应答。一致地，TGR 5缺陷损害先天性抗病毒免疫，而BAs在野生型而不是TGR 5缺陷细胞和小鼠中表现出有效的抗病毒活性。我们的研究结果揭示了细胞内BA代谢在先天性抗病毒免疫中的内在和普遍作用。
The mechanisms on metabolic regulation of immune responses are still elusive. We show here that viral infection induces immediate-early NF-kappa B 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-beta-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.