title: Endogenous HMGB1 regulates autophagy.
abstract: Autophagy clears long-lived proteins and dysfunctional organelles and generates substrates for adenosine triphosphate production during periods of starvation and other types of cellular stress. Here we show that high mobility group box 1 (HMGB1), a chromatin-associated nuclear protein and extracellular damage-associated molecular pattern molecule, is a critical regulator of autophagy. Stimuli that enhance reactive oxygen species promote cytosolic translocation of HMGB1 and thereby enhance autophagic flux. HMGB1 directly interacts with the autophagy protein Beclin1 displacing Bcl-2. Mutation of cysteine 106 (C106), but not the vicinal C23 and C45, of HMGB1 promotes cytosolic localization and sustained autophagy. Pharmacological inhibition of HMGB1 cytoplasmic translocation by agents such as ethyl pyruvate limits starvation-induced autophagy. Moreover, the intramolecular disulfide bridge (C23/45) of HMGB1 is required for binding to Beclin1 and sustaining autophagy. Thus, endogenous HMGB1 is a critical pro-autophagic protein that enhances cell survival and limits programmed apoptotic cell death.
authors.affiliation: Damage Associated Molecular Pattern Molecule Laboratory, Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15219, USA. tangd2@upmc.edu
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Livesey
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Cheh
authors.forename: Adam
authors.initials: A
authors.lastname: Farkas
authors.forename: Patricia
authors.initials: P
authors.lastname: Loughran
authors.forename: George
authors.initials: G
authors.lastname: Hoppe
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D024243:HMGB1 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D034622:RNA Interference; D013217:Starvation / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D024243:HMGB1 Protein
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