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

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.