Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Immunity. 2013 Apr 18;38(4):717-28. doi: 10.1016/j.immuni.2012.12.007.
RIG-I-like receptors (RLRs) sense virus-derived RNA or polyinosinic-polycytidylic acid (poly IC) to exert antiviral immune responses. Here, we examine the mechanisms underlying the adjuvant effects of poly IC. Poly IC was taken up by dendritic cells (DCs), and it induced lysosomal destabilization, which, in turn, activated an RLR-dependent signaling pathway. Upon poly IC stimulation, cathepsin D was released into the cytoplasm from the lysosome to interact with IPS-1, an adaptor molecule for RLRs. This interaction facilitated cathepsin D cleavage of caspase 8 and the activation of the transcription factor NF-κB, resulting in enhanced cytokine production. Further recruitment of the kinase RIP-1 to this complex initiated the necroptosis of a small number of DCs. HMGB1 released by dying cells enhanced IFN-β production in concert with poly IC. Collectively, these findings suggest that cathepsin D-triggered, IPS-1-dependent necroptosis is a mechanism that propagates the adjuvant efficacy of poly IC.
RIG-I 样受体 (RLRs) 可识别病毒衍生的 RNA 或聚肌苷酸-聚胞苷酸 (poly IC)，从而发挥抗病毒免疫反应。在这里，我们研究了 poly IC 佐剂效应的作用机制。Poly IC 被树突状细胞 (DCs)摄取，并诱导溶酶体不稳定，进而激活 RLR 依赖性信号通路。在 poly IC 刺激下，组织蛋白酶 D 从溶酶体释放到细胞质中，与 RLRs 的衔接分子 IPS-1 相互作用。这种相互作用促进了组织蛋白酶 D 对胱天蛋白酶 8 的切割和转录因子 NF-κB 的激活，导致细胞因子的产生增强。激酶 RIP-1 的进一步募集到该复合物中，启动了少数 DCs 的坏死性凋亡。死亡细胞释放的 HMGB1 与 poly IC 协同增强 IFN-β 的产生。总之，这些发现表明，组织蛋白酶 D 触发的、IPS-1 依赖性坏死性凋亡是一种增强 poly IC 佐剂功效的机制。
