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Toll‐like receptor 3 associates with c‐Src tyrosine kinase on endosomes to initiate antiviral signaling
Author(s) -
Johnsen Ingvild Bjellmo,
Nguyen Thuy Thanh,
Ringdal Monika,
Tryggestad Anne Merete,
Bakke Oddmund,
Lien Egil,
Espevik Terje,
Anthonsen Marit W
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601222
Subject(s) - biology , endosome , proto oncogene tyrosine protein kinase src , tyrosine kinase , microbiology and biotechnology , receptor tyrosine kinase , receptor protein tyrosine kinases , signal transduction , receptor , cancer research , biochemistry , intracellular
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.