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

• DOI: 10.1073/pnas.1900748116
• Publication Date: 2019-08-02T22:55:11Z
• Authors: Shuijie Li; Javier Rodriguez; 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; Susanne Schlisio
• Keywords: Wild type

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