Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response
Open Access
- 27 March 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (15), 5791-5796
- https://doi.org/10.1073/pnas.1119238109
Abstract
Toll-like receptor 3 (TLR3) mediates antiviral response by recognizing double-stranded RNA. Its cytoplasmic domain is tyrosine phosphorylated upon ligand binding and initiates downstream signaling via the adapter TIR-containing adaptor inducing interferon–β (TRIF). However, the kinase responsible for TLR3 phosphorylation remains unknown. We show here that Bruton's tyrosine kinase (BTK)-deficient macrophages failed to secrete inflammatory cytokines and IFN-β upon TLR3 stimulation and were impaired in clearing intracellular dengue virus infection. Mutant mice were also less susceptible to d-galactosamine/p(I:C)-induced sepsis. In the absence of BTK, TLR3-induced phosphoinositide 3-kinase (PI3K), AKT and MAPK signaling and activation of NFκB, IRF3, and AP-1 transcription factors were all defective. We demonstrate that BTK directly phosphorylates TLR3 and in particular the critical Tyr759 residue. BTK point mutations that abrogate or led to constitutive kinase activity have opposite effects on TLR3 phosphorylation. Loss of BTK also compromises the formation of the downstream TRIF/receptor-interacting protein 1 (RIP1)/TBK1 complex. Thus, BTK plays a critical role in initiating TLR3 signaling.This publication has 44 references indexed in Scilit:
- Activation of Toll-Like Receptor 3 Impairs the Dengue Virus Serotype 2 Replication through Induction of IFN-β in Cultured Hepatoma CellsPLOS ONE, 2011
- RIG-I, MDA5 and TLR3 Synergistically Play an Important Role in Restriction of Dengue Virus InfectionPLoS Neglected Tropical Diseases, 2011
- The Tyrosine Kinase c-Src Enhances RIG-I (Retinoic Acid-inducible Gene I)-elicited Antiviral SignalingOnline Journal of Public Health Informatics, 2009
- Sensing of Viral Infection and Activation of Innate Immunity by Toll-Like Receptor 3Clinical Microbiology Reviews, 2008
- Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signalingThe EMBO Journal, 2006
- Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profilingImmunological Reviews, 2005
- Bruton's Tyrosine Kinase Is a Toll/Interleukin-1 Receptor Domain-binding Protein That Participates in Nuclear Factor κB Activation by Toll-like Receptor 4Online Journal of Public Health Informatics, 2003
- Double-stranded RNA Signaling by Toll-like Receptor 3 Requires Specific Tyrosine Residues in Its Cytoplasmic DomainOnline Journal of Public Health Informatics, 2003
- Involvement of the IRF family transcription factor IRF‐3 in virus‐induced activation of the IFN‐β geneFEBS Letters, 1998
- Defective B cell development and function in Btk-deficient miceImmunity, 1995