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

Area of Science:

• Immunology
• Molecular Biology
• Cell Signaling

Background:

• Protein tyrosine kinase Src is a key regulator of Toll-like receptor 3 (TLR3)-mediated interferon-beta (IFN-β) synthesis through the TBK1-IFN regulatory factor 3 pathway.
• The precise molecular mechanisms governing Src activity within TLR3 signaling pathways remain incompletely understood.

Purpose of the Study:

• To elucidate the regulatory mechanisms controlling Src activity during TLR3 signaling.
• To identify the role of Glycogen synthase kinase 3 beta (GSK3β) and TNFR-associated factor 2 (TRAF2) in modulating Src function in the context of TLR3-mediated immune responses.

Main Methods:

• Utilized mouse embryonic fibroblasts (MEFs) to investigate polyinosinic:polycytidylic acid (poly(I:C))-induced responses.
• Examined Src phosphorylation at tyrosine 416 and its ubiquitination status.
• Investigated the E3 ligase activity of TRAF2 towards Src.

Main Results:

• GSK3β deficiency in MEFs led to reduced poly(I:C)-induced IFN-β and IFN-stimulated gene expression.
• This reduction was attributed to diminished Src phosphorylation at tyrosine 416.
• Demonstrated that Src undergoes poly(I:C)-dependent lysine 63 chain ubiquitination, with TRAF2 identified as a direct E3 ligase for Src.

Conclusions:

• GSK3β regulates Src phosphorylation via TRAF2-mediated ubiquitination, a novel mechanism in TLR3 signaling.
• The GSK3β-TRAF2-Src axis plays a critical role in TLR3-mediated antiviral responses.
• This finding provides new insights into the molecular regulation of innate antiviral immunity.