Department of Molecular Biophysics and Biochemistry, Yale University , New Haven, CT , USA.
Front Immunol. 2014 Jul 23;5:342. doi: 10.3389/fimmu.2014.00342. eCollection 2014.
Most organisms rely on innate immune receptors to recognize conserved molecular structures from invading microbes. Two essential innate immune receptors, RIG-I and MDA5, detect viral double-stranded RNA in the cytoplasm. The inflammatory response triggered by these RIG-I-like receptors (RLRs) is one of the first and most important lines of defense against infection. RIG-I recognizes short RNA ligands with 5'-triphosphate caps. MDA5 recognizes long kilobase-scale genomic RNA and replication intermediates. Ligand binding induces conformational changes and oligomerization of RLRs that activate the signaling partner MAVS on the mitochondrial and peroxisomal membranes. This signaling process is under tight regulation, dependent on post-translational modifications of RIG-I and MDA5, and on regulatory proteins including unanchored ubiquitin chains and a third RLR, LGP2. Here, we review recent advances that have shifted the paradigm of RLR signaling away from the conventional linear signaling cascade. In the emerging RLR signaling model, large multimeric signaling platforms generate a highly cooperative, self-propagating, and context-dependent signal, which varies with the subcellular localization of the signaling platform.
大多数生物体依赖先天免疫受体来识别入侵微生物的保守分子结构。两种重要的先天免疫受体，RIG-I 和 MDA5，在细胞质中检测病毒双链 RNA。这些 RIG-I 样受体 (RLR) 触发的炎症反应是对抗感染的第一道也是最重要的防线之一。RIG-I 识别具有 5'-三磷酸帽的短 RNA 配体。MDA5 识别长千碱基规模的基因组 RNA 和复制中间体。配体结合诱导 RLR 的构象变化和寡聚化，激活线粒体和过氧化物酶体膜上的信号伙伴 MAVS。这个信号过程受到严格的调控，依赖于 RIG-I 和 MDA5 的翻译后修饰，以及包括无锚定泛素链和第三种 RLR LGP2 的调节蛋白。在这里，我们回顾了最近的进展，这些进展将 RLR 信号的范式从传统的线性信号级联中转移出来。在新兴的 RLR 信号模型中，大型多聚体信号平台产生高度协作、自我传播和上下文相关的信号，该信号随信号平台的亚细胞定位而变化。
