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The ribosomal chaperone NACA recruits PHD2 to cotranslationally modify HIF-α
The EMBO Journal ( IF 9.4 ) Pub Date : 2022-10-11 , DOI: 10.15252/embj.2022112059 Daisheng Song 1 , Kai Peng 1 , Bradleigh E Palmer 1 , Frank S Lee 1
The EMBO Journal ( IF 9.4 ) Pub Date : 2022-10-11 , DOI: 10.15252/embj.2022112059 Daisheng Song 1 , Kai Peng 1 , Bradleigh E Palmer 1 , Frank S Lee 1
Affiliation
Prolyl hydroxylase domain protein 2 (PHD2)-catalyzed modification of hypoxia-inducible factor (HIF)-α is a key event in oxygen sensing. We previously showed that the zinc finger of PHD2 binds to a Pro-Xaa-Leu-Glu (PXLE) motif. Here, we show that the zinc finger binds to this motif in the ribosomal chaperone nascent polypeptide complex-α (NACA). This recruits PHD2 to the translation machinery to cotranslationally modify HIF-α. Importantly, this cotranslational modification is enhanced by a translational pause sequence in HIF-α. Mice with a knock-in Naca gene mutation that abolishes the PXLE motif display erythrocytosis, a reflection of HIF pathway dysregulation. In addition, human erythrocytosis-associated mutations in the zinc finger of PHD2 ablate interaction with NACA. Tibetans, who have adapted to the hypoxia of high altitude, harbor a PHD2 variant that we previously showed displays a defect in zinc finger binding to p23, a PXLE-containing HSP90 cochaperone. We show here that Tibetan PHD2 maintains interaction with NACA, thereby showing differential interactions with PXLE-containing proteins and providing an explanation for why Tibetans are not predisposed to erythrocytosis.
更新日期：2022-10-11
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