On June 14th 2017, Pinglong Xu laboratory published a research article in Cell Host & Microbe entitled “Lck/Hck/Fgr-mediated tyrosine phosphorylation negatively regulates TBK1 to restrain innate antiviral responses”, which describes a novel type of modification on the core kinase TBK1 and its key roles in regulation of innate antiviral immunity.
Cytosolic nucleic acid sensing elicits interferon production for primary antiviral defense through cascades controlled by protein ubiquitination and Ser/Thr phosphorylation. Here we show that TBK1, a core kinase of antiviral pathways, is inhibited by tyrosine phosphorylation. The Src family kinases (SFKs) Lck, Hck and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. Accordingly, antiviral sensing and resistance was substantially enhanced in Lck/Hck/Fgr triple knockout cells and ectopic expression of Lck/Hck/Fgr dampened the antiviral defense in cells and zebrafish. Small molecule inhibitors of SFKs, which are conventional anti-tumor therapeutics, enhanced antiviral responses and protected zebrafish and mice from viral attack. Viral infection induced the expression of Lck/Hck/Fgr through TBK1-mediated mobilization of IRF3, thus constituting a negative feedback loop. These findings unveil the negative regulation of TBK1 via tyrosine phosphorylation and the functional integration of SFKs into innate antiviral immunity.
Lck/Hck/Fgr-mediated tyrosine phosphorylation
negatively regulates TBK1 to restrain innate antiviral responses
Ph.D. (to be) Shengduo Liu and Shasha Chen in Xu laboratory are the first authors, and Dr. Pinglong Xu is the corresponding author of this research article. The study was collaborated by Drs. Xin-Hua Feng, Jian Zou, Zongping Xia, Li Shen, Sheng Ye and other colleagues, sponsored by the NSFC Project (81472665), the MOST 973 plan (2015CB553800) and the National 1000 Young Talents Program, and accomplished in Life Sciences Institute (LSI) at Zhejiang University. Cell Host & Microbe is a sister-issue of Cell and the top tier journal in microbiology, with an IF of 12.552.
Link: http://www.sciencedirect.com/science/article/pii/S1931312817302032
