Raftlin Is Involved in the Nucleocapture Complex to Induce Poly(I:C)-mediated TLR3 Activation
Raftlin Is Involved in the Nucleocapture Complex to Induce Poly(I:C)-mediated TLR3 Activation
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DOI：
10.1074/jbc.m110.185793
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发表时间：
2011-03-25
影响因子：
4.8
通讯作者：
Matsumoto, Misako
中科院分区：
文献类型：
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作者：
Watanabe, Ayako;Tatematsu, Megumi;Matsumoto, Misako
双链RNA类似物poly（I：C）在细胞外激活内体Toll样受体（TLR）3和细胞质RNA解旋酶（黑素瘤分化相关基因5），导致I型干扰素（IFN）和炎性细胞因子的产生。细胞外poly（I：C）被递送到TLR 3阳性细胞器和细胞质的机制仍有待阐明。在这里，我们表明细胞质脂筏蛋白（Raftlin）对于人骨髓树突状细胞和上皮细胞中的poly（I：C）细胞摄取至关重要。当Raftlin被沉默时，poly（I：C）不能进入细胞并且IFN-β产生的诱导被抑制。此外，细胞摄取的B型寡脱氧核苷酸，共享其摄取受体与聚（I：C）抑制Raftlin敲除细胞。在聚（I：C）刺激时，Raftlin从细胞质易位到质膜，在质膜上与poly（I：C）共定位，然后移动到TLR 3阳性内体。因此，Raftlin与摄取受体合作介导poly（I：C）进入细胞，这对TLR 3的活化至关重要。
The double-stranded RNA analog, 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. The mechanism by which extracellular poly(I: C) is delivered to TLR3-positive organelles and the cytoplasm remains to be elucidated. Here, we show that the cytoplasmic lipid raft protein, Raftlin, is essential for poly(I: C) cellular uptake in human myeloid dendritic cells and epithelial cells. When Raftlin was silenced, poly(I: C) failed to enter cells and induction of IFN-beta production was inhibited. In addition, cellular uptake of B-type oligodeoxynucleotide that shares its uptake receptor with poly(I: C) was suppressed in Raftlin knockdown cells. 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. Thus, Raftlin cooperates with the uptake receptor to mediate cell entry of poly(I: C), which is critical for activation of TLR3.