Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing

Song, Daisheng; Li, Lin Sheng; Arsenault, Patrick R.; Tan, Qiulin; Bigham, Abigail W.; Heaton-Johnson, Katherine J.; Master, Stephen R.; Lee, Frank S.

doi:10.1074/jbc.m113.541227

Cited by 67 publications

(80 citation statements)

References 46 publications

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“…It has been observed that the Tibetan (D4E/C127S) PHD2 is markedly defective in its interaction with p23 (Song et al 2014), which would support this model. Interestingly, the defective interaction depends on both the D4E and C127S substitutions (Song et al 2014) and therefore is consistent with the linkage disequilibrium that has been observed for the two SNPs that encode these substitutions (Lorenzo et al 2014;. This model could conceivably provide an explanation for the increased respiratory drive observed in Tibetans.…”

Section: Tibetan Adaptation To High Altitude and Genetic Analysessupporting

confidence: 65%

“…A property of this zinc finger in human PHD2 is that it binds to a Pro-Xaa-Leu-Glu (PXLE) motif (Song et al 2013). This motif is found in select HSP90 cochaperones, such as p23 and FKBP38, as well as HSP90 itself (both HSP90a and HSP90b paralogs) (Song et al 2013(Song et al , 2014. Therefore, the zinc finger of PHD2 is a module that binds to peptides, which is consistent with known functions of other MYND zinc fingers (Matthews et al 2009).…”

Section: The Hif Pathwaysupporting

confidence: 61%

“…Second, the function of the zinc finger in PHD2 may vary in importance in a tissue-specific manner. Third, the zinc finger of PHD2 may differentially use the PXLE motifs of p23, FKBP38, and HSP90; in this regard, it should be noted that the D4E/C127S substitution maintains zinc finger interaction with FKBP38 and HSP90, albeit somewhat more weakly (Song et al 2014). Fourth, PHD2 is deployed in a tissue-specific manner, and the presence of two other PHD paralogs with potentially redundant activity with PHD2 will undoubtedly modulate the impact of PHD2 LOF or GOF.…”

Section: Tibetan Adaptation To High Altitude and Genetic Analysesmentioning

confidence: 99%

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Human high-altitude adaptation: forward genetics meets the HIF pathway

2014

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Humans have adapted to the chronic hypoxia of high altitude in several locations, and recent genome-wide studies have indicated a genetic basis. In some populations, genetic signatures have been identified in the hypoxia-inducible factor (HIF) pathway, which orchestrates the transcriptional response to hypoxia. In Tibetans, they have been found in the HIF2A (EPAS1) gene, which encodes for HIF-2α, and the prolyl hydroxylase domain protein 2 (PHD2, also known as EGLN1) gene, which encodes for one of its key regulators, PHD2. High-altitude adaptation may be due to multiple genes that act in concert with one another. Unraveling their mechanism of action can offer new therapeutic approaches toward treating common human diseases characterized by chronic hypoxia.

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Section: Tibetan Adaptation To High Altitude and Genetic Analysessupporting

confidence: 65%

Section: The Hif Pathwaysupporting

confidence: 61%

Section: Tibetan Adaptation To High Altitude and Genetic Analysesmentioning

confidence: 99%

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Human high-altitude adaptation: forward genetics meets the HIF pathway

2014

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“…This EGLN1 variant has increased hydroxylase activity under hypoxic conditions (10). However, another group studying the EGLN1 D4E/C127S variant demonstrated decreased interaction with the HIF-1α cochaperone p23 that would be expected to result in decreased hydroxylation and up-regulation of HIF α-subunits (12). Intriguingly, the Tibetan EPAS1 haplotype is unique among modern humans and appears to have introgressed from the Neanderthal-related Denisovan genome (11); however, the functional significance of this haplotype remains to be determined.…”

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confidence: 99%

Genetic selection by high altitude: Beware of experiments at ambient conditions

Prchal

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…MYND-type zinc fingers in other proteins typically serve as domains that interact with other proteins (20). For example, the MYND-type zinc finger of the transcriptional regulator ETO binds to a Pro-Pro-Pro-Leu-Ile motif in the corepressor SMRT (21).We have recently shown that the zinc finger of PHD2 binds with high stringency to a Pro-Xaa-Leu-Glu motif that is found in select proteins of the HSP90 pathway, including p23, FKBP38, and HSP90 itself (22,23). This leads to a model in which the zinc finger promotes recruitment of PHD2 to the HSP90 pathway to facilitate hydroxylation of HIF-␣, a known HSP90 client protein.…”

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confidence: 99%

The Zinc Finger of Prolyl Hydroxylase Domain Protein 2 Is Essential for Efficient Hydroxylation of Hypoxia-Inducible Factor α

Arsenault

Song

Chung

et al. 2016

Molecular and Cellular Biology

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bProlyl hydroxylase domain protein 2 (PHD2) (also known as EGLN1) is a key oxygen sensor in mammals that posttranslationally modifies hypoxia-inducible factor ␣ (HIF-␣) and targets it for degradation. In addition to its catalytic domain, PHD2 contains an evolutionarily conserved zinc finger domain, which we have previously proposed recruits PHD2 to the HSP90 pathway to promote HIF-␣ hydroxylation. Here, we provide evidence that this recruitment is critical both in vitro and in vivo. We show that in vitro, the zinc finger can function as an autonomous recruitment domain to facilitate interaction with HIF-␣. In vivo, ablation of zinc finger function by a C36S/C42S Egln1 knock-in mutation results in upregulation of the erythropoietin gene, erythrocytosis, and augmented hypoxic ventilatory response, all hallmarks of Egln1 loss of function and HIF stabilization. Hence, the zinc finger ordinarily performs a critical positive regulatory function. Intriguingly, the function of this zinc finger is impaired in high-altitude-adapted Tibetans, suggesting that their adaptation to high altitude may, in part, be due to a loss-offunction EGLN1 allele. Thus, these findings have important implications for understanding both the molecular mechanism of the hypoxic response and human adaptation to high altitude.T he hypoxia-inducible factor (HIF) pathway is the primary mediator of the transcriptional response to low oxygen (1-3). In this pathway, prolyl hydroxylase domain protein (PHD) site-specifically prolyl hydroxylates hypoxia-inducible factor ␣ (HIF-␣), thereby providing a recognition motif for the von Hippel-Lindau (VHL) protein, which then promotes the ubiquitination and degradation of HIF-␣ (4-6). Under hypoxic conditions, this modification is arrested, leading to the stabilization of HIF-␣, its dimerization with HIF-␤, and the subsequent activation of a transcriptional program that promotes hypoxic adaptation at the organismal and cellular levels (7, 8). There are two main HIF-␣ paralogues, HIF-1␣ and HIF-2␣, which have overlapping and distinct roles. For example, HIF-1␣ promotes glycolysis, whereas HIF-2␣ (also known as EPAS1) regulates the erythropoietin (EPO) gene.In mammals, there are three PHD paralogues (9, 10), and PHD2 has emerged as a particularly important one. For example, knockout of murine Egln1 but not of Egln2 (Phd1) or Egln3 (Phd2) leads to embryonic lethality (11). In humans, heterozygous lossof-function mutations in the EGLN1 gene that impair catalytic activity are a cause of erythrocytosis (12). In mice, acute global deletion of Egln1 leads to marked erythrocytosis (13, 14). Intriguingly, heterozygous loss of Phd2 function in mice leads to increased respiration (15, 16), and importantly, this phenotype is not observed in either Egln2 Ϫ/Ϫ or Egln3 Ϫ/Ϫ mice (15). PHD2 is closely related to the single ancestral PHD that is present in simple metazoans, such as Trichoplax adhaerens (17). This orthologue shares, in addition to a C-terminal prolyl hydroxylase domain, an N-terminal zinc finger that is absent in b...

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Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing

Cited by 67 publications

References 46 publications

Human high-altitude adaptation: forward genetics meets the HIF pathway

Human high-altitude adaptation: forward genetics meets the HIF pathway

Genetic selection by high altitude: Beware of experiments at ambient conditions

The Zinc Finger of Prolyl Hydroxylase Domain Protein 2 Is Essential for Efficient Hydroxylation of Hypoxia-Inducible Factor α

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