Research ArticleCell Biology

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

Science Signaling  08 Nov 2011:
Vol. 4, Issue 198, pp. ra74
DOI: 10.1126/scisignal.2001614

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Apoptosis Induced by dsRNAs

Sequence-specific short interfering RNAs (siRNAs) are double-stranded RNAs (dsRNAs) that knock down the expression of target genes and have been used therapeutically, for example, to treat age-related macular degeneration. Although some of their effects depend on sequence-specific knockdown, some may be mediated by the innate immune system. Thus, a better understanding of cellular responses to various types of dsRNAs may help in the development of better therapies. Ishibashi et al. found that short dsRNAs induced apoptosis in cells derived from a human granulosa cell tumor (an ovarian cancer) without silencing gene expression. Apoptosis depended on the length of the dsRNAs but was independent of their sequence. The short dsRNAs stimulated expression of the gene encoding the cytosolic RNA sensor retinoic acid–inducible protein I (RIG-I). Increasing the abundance of RIG-I rendered previously resistant cells susceptible to dsRNA-induced apoptosis. Despite not having structures characteristic of dsRNAs that are detected by RIG-I, the apoptosis-inducing dsRNAs bound to and activated RIG-I, leading to activation of the kinase p38, which was required for apoptosis. Together, these data suggest an expanded role for cytosolic RNA sensors in mediating cellular responses to dsRNAs.