Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response

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 fo...

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Main Authors: Lee, K.-G., Xu, S., Kang, Z.-H., Huo, J., Huang, M., Liu, D., Takeuchi, O., Lam, K.-P., Akira, Shizuo
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2013
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Online Access:https://hdl.handle.net/10356/98238
http://hdl.handle.net/10220/12357
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spelling sg-ntu-dr.10356-982382023-02-28T17:04:33Z Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response Lee, K.-G. Xu, S. Kang, Z.-H. Huo, J. Huang, M. Liu, D. Takeuchi, O. Lam, K.-P. Akira, Shizuo School of Biological Sciences DRNTU::Science::Biological sciences 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. Published Version 2013-07-26T03:21:37Z 2019-12-06T19:52:26Z 2013-07-26T03:21:37Z 2019-12-06T19:52:26Z 2012 2012 Journal Article Lee, K. G., Xu, S., Kang, Z. H., Huo, J., Huang, M., Liu, D., et al. (2012). Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response. Proceedings of the national academy of sciences, 109(15), 5791-5796. https://hdl.handle.net/10356/98238 http://hdl.handle.net/10220/12357 10.1073/pnas.1119238109 22454496 en Proceedings of the national academy of sciences © 2012 National Academy of Sciences. This paper was published in Proceedings of the national academy of sciences and is made available as an electronic reprint (preprint) with permission of National Academy of Sciences. The paper can be found at the following official OpenURL: [http://dx.doi.org/10.1073/pnas.1119238109]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Biological sciences
spellingShingle DRNTU::Science::Biological sciences
Lee, K.-G.
Xu, S.
Kang, Z.-H.
Huo, J.
Huang, M.
Liu, D.
Takeuchi, O.
Lam, K.-P.
Akira, Shizuo
Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response
description 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.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Lee, K.-G.
Xu, S.
Kang, Z.-H.
Huo, J.
Huang, M.
Liu, D.
Takeuchi, O.
Lam, K.-P.
Akira, Shizuo
format Article
author Lee, K.-G.
Xu, S.
Kang, Z.-H.
Huo, J.
Huang, M.
Liu, D.
Takeuchi, O.
Lam, K.-P.
Akira, Shizuo
author_sort Lee, K.-G.
title Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response
title_short Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response
title_full Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response
title_fullStr Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response
title_full_unstemmed Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response
title_sort bruton's tyrosine kinase phosphorylates toll-like receptor 3 to initiate antiviral response
publishDate 2013
url https://hdl.handle.net/10356/98238
http://hdl.handle.net/10220/12357
_version_ 1759856981525397504