Short RNA duplexes elicit RIG-I-mediated apoptosis in a cell type-and length-dependent manner
Short RNA duplexes elicit RIG-I-mediated apoptosis in a cell type-and length-dependent manner
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短RNA双链体以细胞类型和长度依赖性方式引发RIG-I介导的细胞凋亡
DOI：
10.1126/scisignal.2001614
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发表时间：
2011
期刊：
影响因子：
7.3
通讯作者：
Takizawa T
中科院分区：
文献类型：
--
作者：
Ishibashi O;Ali MM;Luo SS;Ohba T;Katabuchi H;Takeshita T;Takizawa T
短双链 RNA (dsRNA) 诱导 I 型干扰素 (IFN) 介导的先天免疫反应。在体外对短干扰RNA或microRNA前体的合成模拟物进行功能研究时，我们发现短dsRNA很容易诱导人颗粒细胞瘤来源的细胞凋亡，但在其他细胞类型中则不然。细胞凋亡独立于 dsRNA 的序列，但取决于其长度，并且由 23 和 24 核苷酸 (nt) dsRNA 诱导，但不由较短的 dsRNA (<22 nt) 或长 dsRNA 聚肌苷-聚胞苷酸诱导。微阵列分析显示细胞凋亡伴随着IFN刺激基因表达的增加；然而，多项证据表明干扰素并不直接诱导细胞凋亡。随后的分析表明，短 dsRNA 通过 dsRNA 激活蛋白激酶 (PKR) 增加了视黄酸诱导基因 I (RIG-I) 的表达。尽管这些 dsRNA 具有 3' 突出端和非三磷酸 5' 末端（不被认为是 RIG-I 激活结构），但 dsRNA 与 RIG-I 结合并主要通过激活 RIG-I 触发促凋亡信号传导，随后激活丝裂原激活蛋白激酶 p38。因此，我们认为 RNA 传感器的配体识别和随后的信号传导比之前认为的更为复杂。此外，短dsRNA可以作为靶向特定肿瘤（例如颗粒细胞瘤）的药物。
Short double-stranded RNAs (dsRNAs) induce type I interferon (IFN)–mediated innate immune responses. In functional studies with short interfering RNAs or synthetic mimics of microRNA precursors in vitro, we found that short dsRNAs readily induced apoptosis in cells derived from human granulosa cell tumors, but not in other cell types. Apoptosis was independent of the sequence of the dsRNA, but depended on its length, and was induced by 23- and 24-nucleotide (nt) dsRNAs, but not by shorter dsRNAs (<22 nt) or by the long dsRNA polyinosinic-polycytidylic acid. Microarray analysis revealed that apoptosis was accompanied by the increased expression of IFN-stimulated genes; however, several lines of evidence showed that IFNs did not directly induce apoptosis. Subsequent analyses revealed that the short dsRNAs increased the expression ofretinoic acid–inducible gene I(RIG-I) through dsRNA-activated protein kinase (PKR). Although these dsRNAs bore 3′ overhangs and nontriphosphate 5′ termini, which are not thought to be RIG-I–activating structures, the dsRNAs bound to RIG-I and triggered proapoptotic signaling mostly by activating RIG-I, which was followed by activation of the mitogen-activated protein kinase p38. Thus, we suggest that ligand recognition and subsequent signaling by RNA sensors are more complicated than previously believed. In addition, short dsRNAs may serve as pharmacological agents to target specific tumors, such as granulosa cell tumors.