Priming Phosphorylation of TANK-Binding Kinase 1 by IκB Kinase β Is Essential in Toll-Like Receptor 3/4 Signaling.

Abstract:

:TRIF is an essential adaptor for Toll-like receptor 3/4 (TLR3/4) signaling to activate transcription factor interferon regulatory factor 3 (IRF-3). We examined the molecular mechanism of TLR3 signaling and found that TLR3 stimulation by double-stranded RNA (dsRNA) induces phosphorylation of TRIF at Ser210 and is required for IRF-3 recruitment. TANK-binding kinase 1 (TBK1) is known to be responsible for IRF-3 phosphorylation and activation. We found that TBK1 is also responsible for phosphorylation of Ser210 in TRIF. Unexpectedly, we discovered that IκB kinase β (IKKβ) plays an essential role in TLR3/4 signaling using a pharmacological inhibitor and gene deletion. Of note, IKKβ is essential in TLR3/4 but not in retinoic acid-inducible gene I (RIG-I) signaling. Mechanistically, IKKβ transiently associates with and induces the phosphorylation of TBK1 upon TLR3 stimulation. These results suggest a phosphorylation cascade of IKKβ and TBK1, where priming phosphorylation of TBK1 by IKKβ is required to surpass the threshold to induce signaling, thereby activating IRF-3.

journal_name

Mol Cell Biol

authors

Abe H,Satoh J,Shirasaka Y,Kogure A,Kato H,Ito S,Fujita T

doi

10.1128/MCB.00509-19

subject

Has Abstract

pub_date

2020-02-12 00:00:00

issue

5

eissn

0270-7306

issn

1098-5549

pii

MCB.00509-19

journal_volume

40

pub_type

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