The tyrosine kinase c-Src enhances RIG-I (retinoic acid-inducible gene I)-elicited antiviral signaling.
Antiviral immune responses are initiated through Toll-like receptors (TLRs) and RIG-I (retinoic acid-inducible gene-I)-like RNA helicases that recognize nucleic acids from distinct viruses. In this study, we show that the tyrosine kinase c-Src participates in antiviral responses induced by the cytoplasmic RNA helicase RIG-I. Sendai virus (SV), which is recognized by RIG-I, induced c-Src phosphorylation. Functional impairment of c-Src through chemical inhibition or transient expression of a c-Src kinase-inactive mutant attenuated production of endogenous antiviral proteins after SV infection or after expression of RIG-I or its adapter protein MAVS. Importantly, SV-stimulated synthesis of antiviral proteins was significantly impaired in cells treated with c-Src small interfering RNA and in cells from c-Src-deficient mice. In addition, we found that c-Src interacted with components of the RIG-I pathway: RIG-I, MAVS, and TRAF3 (tumor necrosis factor receptor-associated factor-3). The interaction between c-Src and TRAF3 was found to occur within the RING domain of TRAF3. Taken together, our results suggest that c-Src enhances RIG-I-mediated signaling, acting at the level of TRAF3.
Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim N-7006, Norway.
Ingvild B
IB
Johnsen
Thuy Thanh
TT
Nguyen
Bjarte
B
Bergstroem
Katherine A
KA
Fitzgerald
Marit W
MW
Anthonsen
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000378:metabolism; D011971:Receptors, Immunologic; D029082:Sendai virus / Q000378:metabolism; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology*
D000998:Antiviral Agents; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D048008:TNF Receptor-Associated Factor 3; D019061:src-Family Kinases; C452820:RIGI protein, human; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases