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.
Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. Mohammad.Siddiqui@rockets.utoledo.edu.
Mohammad Adnan
MA
Siddiqui
Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. sushovitam@yahoo.com.
Sushovita
S
Mukherjee
Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. Praveen.Manivannan@rockets.utoledo.edu.
Praveen
P
Manivannan
Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. Malathi.Krishnamurthy@utoledo.edu.
Krishnamurthy
K
Malathi
D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics*; D000071186:Beclin-1; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007239:Infections / Q000235:genetics / Q000473:pathology / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000821:virology; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D012330:RNA, Double-Stranded / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D012330:RNA, Double-Stranded; D045304:Cytochromes c; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D053148:Caspase 3
Beclin-1; RNase L; apoptosis; autophagy; dsRNA