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Int. J. Mol. Sci. 2015, 16(8), 17611-17636; doi:10.3390/ijms160817611

RNase L Cleavage Products Promote Switch from Autophagy to Apoptosis by Caspase-Mediated Cleavage of Beclin-1

Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA
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Author to whom correspondence should be addressed.
Academic Editor: Ester Boix
Received: 30 June 2015 / Revised: 17 July 2015 / Accepted: 27 July 2015 / Published: 31 July 2015
(This article belongs to the Special Issue Antimicrobial RNases in Host Defense)
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Abstract

Autophagy and apoptosis share regulatory molecules enabling crosstalk in pathways that affect cellular homeostasis including response to viral infections and survival of tumor cells. Ribonuclease L (RNase L) is an antiviral endonuclease that is activated in virus-infected cells and cleaves viral and cellular single-stranded RNAs to produce small double-stranded RNAs with roles in amplifying host responses. Activation of RNase L induces autophagy and apoptosis in many cell types. However, the mechanism by which RNase L mediates crosstalk between these two pathways remains unclear. Here we show that small dsRNAs produced by RNase L promote a switch from autophagy to apoptosis by caspase-mediated cleavage of Beclin-1, terminating autophagy. The caspase 3-cleaved C-terminal fragment of Beclin-1 enhances apoptosis by translocating to the mitochondria along with proapoptotic protein, Bax, and inducing release of cytochrome C to the cytosol. Cleavage of Beclin-1 determines switch to apoptosis since expression of caspase-resistant Beclin-1 inhibits apoptosis and sustains autophagy. Moreover, inhibiting RNase L-induced autophagy promotes cell death and inhibiting apoptosis prolongs autophagy in a cross-inhibitory mechanism. Our results demonstrate a novel role of RNase L generated small RNAs in cross-talk between autophagy and apoptosis that impacts the fate of cells during viral infections and cancer. View Full-Text
Keywords: autophagy; apoptosis; RNase L; dsRNA; Beclin-1 autophagy; apoptosis; RNase L; dsRNA; Beclin-1
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Siddiqui, M.A.; Mukherjee, S.; Manivannan, P.; Malathi, K. RNase L Cleavage Products Promote Switch from Autophagy to Apoptosis by Caspase-Mediated Cleavage of Beclin-1. Int. J. Mol. Sci. 2015, 16, 17611-17636.

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