title: Regulation of ULK1 Expression and Autophagy by STAT1.
abstract: Autophagy involves the lysosomal degradation of cytoplasmic contents for regeneration of anabolic substrates during nutritional or inflammatory stress. Its initiation occurs rapidly after inactivation of the protein kinase mammalian target of rapamycin (mTOR) (or mechanistic target of rapamycin), leading to dephosphorylation of Unc-51-like kinase 1 (ULK1) and autophagosome formation. Recent studies indicate that mTOR can, in parallel, regulate the activity of stress transcription factors, including signal transducer and activator of transcription-1 (STAT1). The current study addresses the role of STAT1 as a transcriptional suppressor of autophagy genes and autophagic activity. We show that STAT1-deficient human fibrosarcoma cells exhibited enhanced autophagic flux as well as its induction by pharmacological inhibition of mTOR. Consistent with enhanced autophagy initiation, ULK1 mRNA and protein levels were increased in STAT1-deficient cells. By chromatin immunoprecipitation, STAT1 bound a putative regulatory sequence in the ULK1 5'-flanking region, the mutation of which increased ULK1 promoter activity, and rendered it unresponsive to mTOR inhibition. Consistent with an anti-apoptotic effect of autophagy, rapamycin-induced apoptosis and cytotoxicity were blocked in STAT1-deficient cells but restored in cells simultaneously exposed to the autophagy inhibitor ammonium chloride. In vivo, skeletal muscle ULK1 mRNA and protein levels as well as autophagic flux were significantly enhanced in STAT1-deficient mice. These results demonstrate a novel mechanism by which STAT1 negatively regulates ULK1 expression and autophagy.
authors.affiliation: From the Departments of Critical Care and Medicine, McGill University Health Centre and Meakins-Christie Laboratories, McGill University, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Goldberg
authors.affiliation: From the Departments of Critical Care and Medicine, McGill University Health Centre and Meakins-Christie Laboratories, McGill University, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Nkengfac
authors.affiliation: From the Departments of Critical Care and Medicine, McGill University Health Centre and Meakins-Christie Laboratories, McGill University, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Anthony M J
authors.initials: AMJ
authors.lastname: Sanchez
authors.affiliation: From the Departments of Critical Care and Medicine, McGill University Health Centre and Meakins-Christie Laboratories, McGill University, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Moroz
authors.affiliation: From the Departments of Critical Care and Medicine, McGill University Health Centre and Meakins-Christie Laboratories, McGill University, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Salman T
authors.initials: ST
authors.lastname: Qureshi
authors.affiliation: the Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
authors.affiliation: the Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Faculty of Pharmacy, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Burelle
authors.affiliation: From the Departments of Critical Care and Medicine, McGill University Health Centre and Meakins-Christie Laboratories, McGill University, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Sabah N
authors.initials: SN
authors.lastname: Hussain
authors.affiliation: From the Departments of Critical Care and Medicine, McGill University Health Centre and Meakins-Christie Laboratories, McGill University, Montreal, Quebec H4A 3J1, Canada. Electronic address: arnold.kristof@mcgill.ca.
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Kristof
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071189:Autophagy-Related Protein-1 Homolog / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D000071189:Autophagy-Related Protein-1 Homolog; C484754:ULK1 protein, human; C112444:Ulk1 protein, mouse; D020123:Sirolimus
keywords: apoptosis; autophagy; mammalian target of rapamycin (mTOR); proteolysis; signal transducers and activators of transcription 1 (STAT1)