Mechanism of nucleic acid recognition by endosomal Toll-like receptor 3

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The synthetic virus double-stranded RNA analogue, poly (I:C), extracellularly activates both the endosomal Toll-like receptor (TLR) 3 and the cytoplasmic RNA helicase, melanoma differentiation-associated gene 5, leading to the production of type I interferons (IFNs) and inflammatory cytokines, and dendritic cell (DC) maturation. The mechanism by which extracellular poly(I:C) is delivered to TLR3-positive organelles and the cytoplasm remains to be elucidated. In this study, we demonstrate that the cytoplasmic lipid raft protein, Raftlin, is essential for poly (I:C) cellular uptake in human myeloid DCs and epithelial cells. When Raftlin was silenced, poly (I:C) failed to enter cells and induction of IFN-β production was inhibited. Upon poly (I:C) stimulation, Raftlin was translocated from the cytoplasm to the plasma membrane where it colocalized with poly (I:C), and thereafter moved to TLR3-positive endosomes. Raftlin physically associated with clathrin at the plasma membrane in response to poly (I:C). Thus, Raftlin cooperates with the clathrin-AP-2 complex to mediate cell entry of poly (I:C), which is critical for activation of TLR3.