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Sci. Signal., 8 November 2011
Vol. 4, Issue 198, p. ra74
[DOI: 10.1126/scisignal.2001614]

RESEARCH ARTICLES

Short RNA Duplexes Elicit RIG-I–Mediated Apoptosis in a Cell Type– and Length-Dependent Manner

Osamu Ishibashi1, Md. Moksed Ali1, Shan-Shun Luo1,2, Takashi Ohba3, Hidetaka Katabuchi3, Toshiyuki Takeshita4, and Toshihiro Takizawa1*

1 Department of Molecular Medicine and Anatomy, Nippon Medical School, 1-1-5 Sendagi, Tokyo 113-8602, Japan.
2 Department of Cardiology, First Clinical College of Harbin Medical University, Harbin, Heilongjiang 150001, China.
3 Department of Gynecology, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
4 Department of Obstetrics and Gynecology, Nippon Medical School, 1-1-5 Sendagi, Tokyo 113-8602, Japan.

Abstract: 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 of retinoic 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.

* To whom correspondence should be addressed. E-mail: t-takizawa{at}nms.ac.jp

Citation: O. Ishibashi, M. M. Ali, S.-S. Luo, T. Ohba, H. Katabuchi, T. Takeshita, T. Takizawa, Short RNA Duplexes Elicit RIG-I–Mediated Apoptosis in a Cell Type– and Length-Dependent Manner. Sci. Signal. 4, ra74 (2011).

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