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Lck/Hck/Fgr-Mediated Tyrosine Phosphorylation Negatively Regulates TBK1 to Restrain Innate Antiviral Responses.
- Source :
-
Cell host & microbe [Cell Host Microbe] 2017 Jun 14; Vol. 21 (6), pp. 754-768.e5. - Publication Year :
- 2017
-
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.<br /> (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Subjects :
- Adaptor Proteins, Signal Transducing metabolism
Animals
Antiviral Agents metabolism
Cell Line
Chlorocebus aethiops
Cytosol immunology
Cytosol metabolism
HEK293 Cells
Hep G2 Cells
Herpesvirus 1, Human
Humans
Interferon Regulatory Factor-3 metabolism
Male
Mice
Mice, Inbred C57BL
Phosphorylation
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-hck metabolism
Respirovirus Infections immunology
Rhabdoviridae Infections immunology
Sendai virus pathogenicity
Ubiquitination
Vero Cells
Vesiculovirus
Zebrafish immunology
Zebrafish Proteins metabolism
src-Family Kinases metabolism
Antiviral Agents immunology
Immunity, Innate
Protein Serine-Threonine Kinases metabolism
Tyrosine metabolism
Virus Diseases immunology
src-Family Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1934-6069
- Volume :
- 21
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell host & microbe
- Publication Type :
- Academic Journal
- Accession number :
- 28618271
- Full Text :
- https://doi.org/10.1016/j.chom.2017.05.010