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NPGPx modulates CPEB2-controlled HIF-1? 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-1?) RNA translation. In NPGPx-proficient cells, high oxidative stress that disrupts this bonding compromises the association of CPEB2 with HIF-1? RNA, leading to elevated HIF-1? RNA translation. NPGPx-deficient cells, in contrast, demonstrate increased HIF-1? RNA translation under normoxia with both impaired induction of HIF-1? synthesis and blunted HIF-1?-programmed transcription following oxidative stress. Together, these results reveal a molecular mechanism for how NPGPx mediates CPEB2-controlled HIF-1? RNA translation in a redox-sensitive manner.

SUBMITTER: Chen PJ

PROVIDER: S-EPMC4627054 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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NPGPx modulates CPEB2-controlled HIF-1α RNA translation in response to oxidative stress.

Chen Po-Jen PJ Weng Jui-Yun JY Hsu Pang-Hung PH Shew Jin-Yuh JY Huang Yi-Shuian YS Lee Wen-Hwa WH

Nucleic acids research 20151007 19

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 t ...[more]

PMID: 26446990

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Project description:BackgroundEndothelial cell (EC) injury accelerates the progression of diabetic macrovascular complications. Hypoxia is an important cause of EC injury. Hypoxia-inducible factor-1 alpha (HIF-1α) is an important hypoxia regulatory protein. Our previous studies showed that high-glucose and hypoxic conditions could upregulate HIF-1α expression and enhance EC inflammatory injury, independently of the nuclear factor kappa-B (NF-κB) pathway. However, it is not clear whether HIF-1α plays a role in vascular disease through epigenetic-related mechanisms.MethodsWe conducted gene expression analysis and molecular mechanistic studies in human umbilical vein endothelial cells (HUVECs) induced by hyperglycemia and hypoxia using RNA sequencing (RNA-seq) and small interfering HIF-1α (si-HIF-1α). We determined HIF-1α and Jumonji domain-containing protein 1 A (JMJD1A) expression by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, analyzed inflammatory protein secretion in the cell supernatant by enzymelinked immunosorbent assay (ELISA), and assessed protein interaction between HIF-1α and JMJD1A by chromatin immunoprecipitation (Ch-IP). We used the Cell Counting Kit8 (CCK-8) assay to analyze cell viability, and assessed oxidative stress indicators by using a detection kit and flow cytometry.ResultsHigh glucose and hypoxia up-regulated HIF-1α expression, and down-regulated HIF-1α decreased the level of inflammation and oxidative stress in HUVECs. To determine the downstream pathways, we observed histone demethylases genes and related pathway by RNA-sEq. Among these, JMJD1A was the most upregulated gene in histone demethylases. Moreover, we observed that HIF-1α bound to the promoter of JMJD1A, and the ameliorative effects of si-HIF-1α on oxidative stress and inflammatory cytokines in high-glucose and hypoxia-induced HUVECs were reversed by JMJD1A overexpression. Furthermore, knockdown of JMJD1A decreased inflammatory and oxidative stress injury. To determine the JMJD1A-related factors, we conducted gene expression analysis on JMJD1A-knockdown HUVECs. We observed that downregulation of inflammation and the oxidative stress pathway were enriched and FOS and FOSB might be important protective transcription factors.ConclusionsThese findings provide novel evidence that the HIF-1α/JMJD1A signaling pathway is involved in inflammation and oxidative stress in HUVECs induced by high glucose and hypoxia. Also, this pathway might act as a novel regulator of oxidative stress and inflammatory-related events in response to diabetic vascular injury and thus contribute to the pathological progression of diabetes and vascular disease.

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NPGPx modulates CPEB2-controlled HIF-1? RNA translation in response to oxidative stress.

Publications

NPGPx modulates CPEB2-controlled HIF-1α RNA translation in response to oxidative stress.

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