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

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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.