title: NPGPx modulates CPEB2-controlled HIF-1α RNA translation in response to oxidative stress.
abstract: Non-selenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx or GPx7) is an oxidative stress sensor that modulates the antioxidative activity of its target proteins through intermolecular disulfide bond formation. Given NPGPx's role in protecting cells from oxidative damage, identification of the oxidative stress-induced protein complexes, which forms with key stress factors, may offer novel insight into intracellular reactive oxygen species homeostasis. Here, we show that NPGPx forms a disulfide bond with the translational regulator cytoplasmic polyadenylation element-binding protein 2 (CPEB2) that results in negative regulation of hypoxia-inducible factor 1-alpha (HIF-1α) RNA translation. In NPGPx-proficient cells, high oxidative stress that disrupts this bonding compromises the association of CPEB2 with HIF-1α RNA, leading to elevated HIF-1α RNA translation. NPGPx-deficient cells, in contrast, demonstrate increased HIF-1α RNA translation under normoxia with both impaired induction of HIF-1α synthesis and blunted HIF-1α-programmed transcription following oxidative stress. Together, these results reveal a molecular mechanism for how NPGPx mediates CPEB2-controlled HIF-1α RNA translation in a redox-sensitive manner.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Po-Jen
authors.initials: PJ
authors.lastname: Chen
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Jui-Yun
authors.initials: JY
authors.lastname: Weng
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Pang-Hung
authors.initials: PH
authors.lastname: Hsu
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Jin-Yuh
authors.initials: JY
authors.lastname: Shew
authors.affiliation: Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, 20224, Taiwan yishuian@ibms.sinica.edu.tw.
authors.forename: Yi-Shuian
authors.initials: YS
authors.lastname: Huang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan Graduate Institute of Clinical Medicine, China Medical University, Taichung 40402, Taiwan whlee@uci.edu.
authors.forename: Wen-Hwa
authors.initials: WH
authors.lastname: Lee
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D003545:Cysteine / Q000032:analysis; D004220:Disulfides / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018384:Oxidative Stress; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D014158:Transcription, Genetic
chemical_list: C554938:CPEB2 protein, human; D002352:Carrier Proteins; D004220:Disulfides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C578349:NPGPx protein, mouse; D016601:RNA-Binding Proteins; D003545:Cysteine