Molecular mechanism by which extracellular RNA activates Toll-like receptor 3

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Toll-like receptor (TLR) 3 recognizes dsRNA in the endosomes and induces type I interferon and proinflammatory cytokine production, and dendritic cell (DC) maturation via the adaptor protein TICAM-1. The mechanism by which extracellular dsRNA is delivered to TLR3-positive organelles remains to be elucidated. In this study, we demonstrate that TLR3 recognizes virus-derived ssRNAs with stable stem structures, in addition to dsRNA, and that the cytoplasmic lipid raft protein, Raftlin, is essential for dsRNA/ssRNA cellular uptake in human myeloid DCs and epithelial cells. Raftlin physically associates with clathrin at the plasma membrane in response to dsRNA and mediates cell entry of dsRNA/ssRNA, which is critical for activation of TLR3. Hence, both cell-surface and endosomal recognition of RNAs by the uptake receptor and TLR3, respectively, is required for TLR3 activation.