Key Points
GSK3β interacts with Src tyrosine kinase.
Src positively regulates antiviral immune response.
Src undergoes K63-linked ubiquitination by TRAF2.
Abstract
The protein tyrosine kinase Src regulates the synthesis of TLR3-mediated IFN-β via the TBK1–IFN regulatory factor 3 axis. However, the molecular mechanisms regulating Src activity in TLR3 signaling remain unclear. In this study, we report that GSK3β regulates Src phosphorylation via TNFR-associated factor 2 (TRAF2)–mediated Src ubiquitination. GSK3β deficiency in mouse embryonic fibroblasts significantly reduces polyinosinic:polycytidylic acid–induced IFN-β and IFN-stimulated gene expression, which is caused by diminished phosphorylation of Src at tyrosine 416. Src undergoes polyinosinic:polycytidylic acid–dependent lysine 63 chain ubiquitination, and TRAF2 is a direct E3 ligase for Src. Our study reveals novel mechanisms underlying TLR3-mediated antiviral responses mediated via the GSK3β–TRAF2–Src axis.
Footnotes
This work was supported by National Research Foundation of Korea Grants 2019R1A5A6099645 and 2016R1A2B3010699 (to S.Y.L.) and 2015R1A6A3A01020489 and 2017R1A6A3A11034079 (to R.K.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- BMDM
- bone marrow–derived macrophage
- Con
- control shRNA
- EV
- empty vector
- GSK3β
- glycogen synthase kinase 3β
- IRF3
- IFN regulatory factor 3
- ISG
- IFN-stimulated gene
- MEF
- mouse embryonic fibroblast
- PK
- protein kinase
- poly I:C
- polyinosinic:polycytidylic acid
- SH
- Src homology
- shRNA
- short hairpin RNA
- siRNA
- small interfering RNA
- TBK1
- TANK-binding kinase 1
- TRAF
- TNFR-associated factor
- TRIF
- TIR domain–containing adapter, including IFN-β
- WT
- wild-type.
- Received June 20, 2019.
- Accepted September 23, 2019.
- Copyright © 2019 by The American Association of Immunologists, Inc.
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