title: BNIP3 is degraded by ULK1-dependent autophagy via MTORC1 and AMPK.
abstract: BNIP3 (BCL2/adenovirus E1B 19 kDa interacting protein 3) is an atypical BH3-only protein that is induced by hypoxia-inducible factor 1 (HIF1) under hypoxia. BNIP3 is primarily regulated at the transcriptional level. However, little is known about the underlying mechanism of BNIP3 degradation. In this study, we found that BNIP3 was downregulated when hypoxia was accompanied by amino acid starvation. The BNIP3 downregulation did not occur at the transcription level and was independent of HIF1A. BNIP3 was primarily degraded by the proteasome, but BNIP3 was subjected to both proteasomal and autophagic degradation in response to starvation. The autophagic degradation of BNIP3 was dependent on ATG7 and MAP1LC3. We determined that autophagic degradation of BNIP3 was specifically regulated by ULK1 via the MTOR-AMPK pathway. Moreover, we confirmed that BNIP3 could play a protective role in tumor cells under hypoxia, and the treatment with Torin1, an MTOR inhibitor, decreased the BNIP3 level and enhanced the death of hypoxic tumor cells.
authors.affiliation: Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, South Korea.
authors.forename: Chang Wook
authors.initials: CW
authors.lastname: Park
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Hong
authors.forename: Eung-Sam
authors.initials: ES
authors.lastname: Kim
authors.forename: Jung Hee
authors.initials: JH
authors.lastname: Kwon
authors.forename: Kyong-Tai
authors.initials: KT
authors.lastname: Kim
authors.forename: Hong Gil
authors.initials: HG
authors.lastname: Nam
authors.forename: Kwan Yong
authors.initials: KY
authors.lastname: Choi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D015687:Cell Hypoxia; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C090121:BNIP3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; D000071189:Autophagy-Related Protein-1 Homolog; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human; D055372:AMP-Activated Protein Kinases
keywords: AMPK; BECN1; BNIP3; MTOR; Torin1; ULK1; autophagy; hypoxia