PUBLICATION
Lck/Hck/Fgr-Mediated Tyrosine Phosphorylation Negatively Regulates TBK1 to Restrain Innate Antiviral Responses
- Authors
- Liu, S., Chen, S., Li, X., Wu, S., Zhang, Q., Jin, Q., Hu, L., Zhou, R., Yu, Z., Meng, F., Wang, S., Huang, Y., Ye, S., Shen, L., Xia, Z., Zou, J., Feng, X.H., Xu, P.
- ID
- ZDB-PUB-170616-3
- Date
- 2017
- Source
- Cell Host & Microbe 21: 754-768.e5 (Journal)
- Registered Authors
- Zou, Jian
- Keywords
- IRF3, Src family kinase, TBK1, antiviral response, cytosolic nucleic acid sensing, innate immunity, kinase inhibitor, protein modification, tyrosine phosphorylation, zebrafish
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/metabolism
- Animals
- Antiviral Agents/immunology*
- Antiviral Agents/metabolism
- Cell Line
- Chlorocebus aethiops
- Cytosol/immunology
- Cytosol/metabolism
- HEK293 Cells
- Hep G2 Cells
- Herpesvirus 1, Human
- Humans
- Immunity, Innate*
- Interferon Regulatory Factor-3/metabolism
- Male
- Mice
- Mice, Inbred C57BL
- Phosphorylation
- Protein Serine-Threonine Kinases/metabolism*
- Proto-Oncogene Proteins/metabolism
- Proto-Oncogene Proteins c-hck/metabolism
- Respirovirus Infections/immunology
- Rhabdoviridae Infections/immunology
- Sendai virus/pathogenicity
- Tyrosine/metabolism*
- Ubiquitination
- Vero Cells
- Vesiculovirus
- Virus Diseases/immunology*
- Zebrafish/immunology
- Zebrafish Proteins/metabolism
- src-Family Kinases/antagonists & inhibitors*
- src-Family Kinases/metabolism
- PubMed
- 28618271 Full text @ Cell Host Microbe
Citation
Liu, S., Chen, S., Li, X., Wu, S., Zhang, Q., Jin, Q., Hu, L., Zhou, R., Yu, Z., Meng, F., Wang, S., Huang, Y., Ye, S., Shen, L., Xia, Z., Zou, J., Feng, X.H., Xu, P. (2017) Lck/Hck/Fgr-Mediated Tyrosine Phosphorylation Negatively Regulates TBK1 to Restrain Innate Antiviral Responses. Cell Host & Microbe. 21:754-768.e5.
Abstract
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 were 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping