title: miR-376b controls starvation and mTOR inhibition-related autophagy by targeting ATG4C and BECN1.
abstract: Macroautophagy (autophagy) is the major intracellular degradation pathway for long-lived proteins and organelles. It helps the cell to survive a spectrum of stressful conditions including starvation, growth factor deprivation and misfolded protein accumulation. Moreover, abnormalities of autophagy play a role in major health problems including cancer and neurodegenerative diseases. Yet, mechanisms controlling autophagic activity are not fully understood. Here, we describe hsa-miR-376b (miR-376b) as a new microRNA (miRNA) regulating autophagy. We showed that miR-376b expression attenuated starvation- and rapamycin-induced autophagy in MCF-7 and Huh-7 cells. We discovered autophagy proteins ATG4C and BECN1 (Beclin 1) as cellular targets of miR-376b. Indeed, upon miRNA overexpression, both mRNA and protein levels of ATG4C and BECN1 were decreased. miR-376b target sequences were present in the 3' UTR of ATG4C and BECN1 mRNAs and introduction of mutations abolished their miR-376b responsiveness. Antagomir-mediated inactivation of the endogenous miR-376b led to an increase in ATG4C and BECN1 levels. Therefore, miR-376b controls autophagy by directly regulating intracellular levels of two key autophagy proteins, ATG4C and BECN1.
authors.affiliation: Faculty of Engineering and Natural Sciences, Biological Sciences and Bioengineering Program, Sabanci University, Orhanli-Tuzla, Istanbul, Turkey.
authors.forename: Gozde
authors.initials: G
authors.lastname: Korkmaz
authors.forename: Carlos
authors.initials: C
authors.lastname: le Sage
authors.forename: Kumsal Ayse
authors.initials: KA
authors.lastname: Tekirdag
authors.forename: Reuven
authors.initials: R
authors.lastname: Agami
authors.forename: Devrim
authors.initials: D
authors.lastname: Gozuacik
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects; D000071183:Autophagy-Related Proteins; D001483:Base Sequence; D000071186:Beclin-1; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009843:Oligoribonucleotides / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D000071456:Sequestosome-1 Protein; D020123:Sirolimus / Q000494:pharmacology; D013217:Starvation; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000071183:Autophagy-Related Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C573498:MIRN376C microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D009843:Oligoribonucleotides; D012333:RNA, Messenger; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C474025:ATG4A protein, human; D003546:Cysteine Endopeptidases; D020123:Sirolimus