Heir P, Srikumar T, Bikopoulos G, Bunda S, Poon BP, Lee JE, Raught B, Ohh M

von Hippel-Lindau (VHL) disease is a rare familial cancer predisposition syndrome caused by a loss or mutation in a single gene, VHL, but exhibits a wide phenotypic variability that can be categorized into distinct subtypes. The phenotypic variability has been largely argued to be attributable to the extent of deregulation ...

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of the α subunit of hypoxia-inducible factor (HIFα), a well-established target of VHL E3 ubiquitin ligase, ECV (Elongins/Cul2/VHL). Here, we show that erythropoietin receptor (EPOR) is hydroxylated on proline 419 and 426 via prolyl hydroxylase 3 (PHD3). EPOR hydroxylation is required for binding to the β domain of VHL and polyubiquitylation via ECV leading to increased EPOR turnover. In addition, several type-specific VHL disease-causing mutants, including those that have retained proper binding and regulation of HIFα, showed a severe defect in binding prolyl hydroxylated EPOR peptides. These results identify EPOR as the second bona fide hydroxylation dependent substrate of VHL that potentially influences oxygen homeostasis and contributes to the complex genotype-phenotype correlation in VHL disease.

Date: Feb. 04, 2016

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