1. Academic Validation
  2. Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling

Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling

  • EMBO J. 2006 Jul 26;25(14):3335-46. doi: 10.1038/sj.emboj.7601222.
Ingvild Bjellmo Johnsen 1 Thuy Thanh Nguyen Monika Ringdal Anne Merete Tryggestad Oddmund Bakke Egil Lien Terje Espevik Marit W Anthonsen
Affiliations

Affiliation

  • 1 Department of Laboratory Medicine, Children's and Women's Health, Institute of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway. ingvild.Johnsen@ntnu.no
Abstract

Double-stranded RNA (dsRNA) is produced during the replication cycle of most viruses and triggers Antiviral immune responses through Toll-like Receptor 3 (TLR3). However, the molecular mechanisms and subcellular compartments associated with dsRNA-TLR3-mediated signaling are largely unknown. Here we show that c-Src tyrosine kinase is activated by dsRNA in human monocyte-derived dendritic cells, and is recruited to TLR3 in a dsRNA-dependent manner. DsRNA-induced activation of interferon-regulatory factor 3 and signal transducer and activator of transcription 1 was abolished in Src kinase-deficient cells, and restored by adding back c-Src, suggesting a central role of c-Src in Antiviral immunity. We also provide evidence that TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA, and colocalizes with c-Src on endosomes containing dsRNA in the lumen. These results provide novel insight into the molecular mechanisms of TLR3-mediated signaling, which may contribute to the understanding of innate immune responses during viral infections.

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