EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance

Shuijie Li, Javier Rodriguez Martinez, Wenyu Li, Petra Bullova, Stuart M Fell, Olga Surova, Isabelle Westerlund, Danijal Topcic, Maria Bergsland, Adam Stenman, Jonas Muhr, Monica Nistér, Johan Holmberg, C.Christofer Juhlin, Catharina Larsson, Alex von Kriegsheim, William G Kaelin Jr, Susanne Schlisio

Research output: Contribution to journalArticlepeer-review

Abstract

Despite the discovery of the oxygen-sensitive regulation of HIFα by the von Hippel–Lindau (VHL) protein, the mechanisms underlying the complex genotype/phenotype correlations in VHL disease remain unknown. Some germline VHL mutations cause familial pheochromocytoma and encode proteins that preserve their ability to down-regulate HIFα. While type 1, 2A, and 2B VHL mutants are defective in regulating HIFα, type 2C mutants encode proteins that preserve their ability to down-regulate HIFα. Here, we identified an oxygen-sensitive function of VHL that is abolished by VHL type 2C mutations. We found that BIM-EL, a proapoptotic BH3-only protein, is hydroxylated by EglN3 and subsequently bound by VHL. VHL mutants fail to bind hydroxylated BIM-EL, regardless of whether they have the ability to bind hydroxylated HIFα or not. VHL binding inhibits BIM-EL phosphorylation by extracellular signal-related kinase (ERK) on serine 69. This causes BIM-EL to escape from proteasomal degradation, allowing it to enhance EglN3-induced apoptosis. BIM-EL was rapidly degraded in cells lacking wild-type VHL or in which EglN3 was inactivated genetically or by lack of oxygen, leading to enhanced cell survival and chemotherapy resistance. Combination therapy using ERK inhibitors, however, resensitizes VHL- and EglN3-deficient cells that are otherwise cisplatin-resistant.
Original languageEnglish
JournalProceedings of the National Academy of Sciences
Volume116
Issue number34
Early online date2 Aug 2019
DOIs
Publication statusPublished - 20 Aug 2019

Keywords

  • pheochromocytoma
  • paragangliona
  • VHL-type-2C
  • O2-sensing
  • prolyl
  • hydroxylation
  • EGLN3
  • apoptosis

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