title: RNase L triggers autophagy in response to viral infections.
abstract: Autophagy is a programmed homeostatic response to diverse types of cellular stress that disposes of long-lived proteins, organelles, and invading microbes within double-membraned structures called autophagosomes. The 2',5'-oligoadenylate/RNase L system is a virus-activated host RNase pathway that disposes of or processes viral and cellular single-stranded RNAs. Here we report that activation of RNase L during viral infections induces autophagy. Accordingly, infections with encephalomyocarditis virus or vesicular stomatitis virus led to higher levels of autophagy in wild-type mouse embryonic fibroblasts (MEF) than in RNase L-null MEF. Similarly, direct activation of RNase L with a 2',5'-oligoadenylate resulted in p62(SQSTM1) degradation, LC3BI/LC3BII conversion, and appearance of autophagosomes. To determine the effect of RNase L-mediated autophagy on viral replication, we compared viral yields in wild-type and RNase L-null MEF in the absence or presence of either chemical inhibitors of autophagy (bafilomycin A1 or 3-methyladenine) or small interfering RNA (siRNA) against ATG5 or beclin-1. At a low multiplicity of infection, induction of autophagy by RNase L during the initial cycle of virus growth contributed to the suppression of virus replication. However, in subsequent rounds of infection, autophagy promoted viral replication, reducing the antiviral effect of RNase L. Our results indicate a novel function of RNase L as an inducer of autophagy that affects viral yields.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Arindam
authors.initials: A
authors.lastname: Chakrabarti
authors.forename: Prabar Kumar
authors.initials: PK
authors.lastname: Ghosh
authors.forename: Shuvojit
authors.initials: S
authors.lastname: Banerjee
authors.forename: Christina
authors.initials: C
authors.lastname: Gaughan
authors.forename: Robert H
authors.initials: RH
authors.lastname: Silverman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004686:Encephalomyocarditis virus / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism*; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; D014721:Vesicular stomatitis Indiana virus / Q000502:physiology*; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D006360:Heat-Shock Proteins; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C025946:3-methyladenine; C040929:bafilomycin A1; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D000225:Adenine