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Glycogen Synthase Kinase 3β Regulates Antiviral Responses of TLR3 via TRAF2–Src Axis

Ryeojin Ko, Hana Park, Nawon Lee, Jeongin Seo, Woojin Jeong and Soo Young Lee
J Immunol December 1, 2019, 203 (11) 2990-2999; DOI: https://doi.org/10.4049/jimmunol.1900685
Ryeojin Ko
Department of Life Science, Ewha Womans University, Seoul 03760, Korea; andThe Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 03760, Korea
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Hana Park
Department of Life Science, Ewha Womans University, Seoul 03760, Korea; and
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Nawon Lee
Department of Life Science, Ewha Womans University, Seoul 03760, Korea; and
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Jeongin Seo
Department of Life Science, Ewha Womans University, Seoul 03760, Korea; and
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Woojin Jeong
Department of Life Science, Ewha Womans University, Seoul 03760, Korea; andThe Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 03760, Korea
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Soo Young Lee
Department of Life Science, Ewha Womans University, Seoul 03760, Korea; andThe Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 03760, Korea
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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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The Journal of Immunology: 203 (11)
The Journal of Immunology
Vol. 203, Issue 11
1 Dec 2019
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Glycogen Synthase Kinase 3β Regulates Antiviral Responses of TLR3 via TRAF2–Src Axis
Ryeojin Ko, Hana Park, Nawon Lee, Jeongin Seo, Woojin Jeong, Soo Young Lee
The Journal of Immunology December 1, 2019, 203 (11) 2990-2999; DOI: 10.4049/jimmunol.1900685

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Glycogen Synthase Kinase 3β Regulates Antiviral Responses of TLR3 via TRAF2–Src Axis
Ryeojin Ko, Hana Park, Nawon Lee, Jeongin Seo, Woojin Jeong, Soo Young Lee
The Journal of Immunology December 1, 2019, 203 (11) 2990-2999; DOI: 10.4049/jimmunol.1900685
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