The ribosomal chaperone NACA recruits PHD2 to cotranslationally modify HIF-α

Area of Science:

• Biochemistry
• Molecular Biology
• Physiology

Background:

• Prolyl hydroxylase domain protein 2 (PHD2) regulates hypoxia-inducible factor-α (HIF-α) stability, a crucial step in oxygen sensing.
• PHD2's zinc finger domain previously demonstrated binding to Pro-Xaa-Leu-Glu (PXLE) motifs.

Purpose of the Study:

• To investigate the interaction between PHD2 and the ribosomal chaperone nascent polypeptide complex-α (NACA).
• To elucidate the role of this interaction in the cotranslational modification of HIF-α and its implications for oxygen homeostasis and adaptation to hypoxia.

Main Methods:

• Investigated PHD2-NACA interaction using biochemical assays.
• Analyzed the effect of a Naca gene mutation abolishing the PXLE motif in mice.
• Examined PHD2 variants from Tibetan populations with high-altitude adaptation.

Main Results:

• PHD2's zinc finger binds to the PXLE motif in NACA, recruiting PHD2 to the translation machinery for cotranslational HIF-α modification.
• A mouse model with a mutated Naca PXLE motif exhibited erythrocytosis, indicating HIF pathway dysregulation.
• Human PHD2 mutations linked to erythrocytosis impaired NACA interaction, while Tibetan PHD2 variants retained NACA interaction despite altered p23 binding.

Conclusions:

• PHD2's cotranslational modification of HIF-α, facilitated by NACA, is a key regulatory mechanism.
• Differential interactions of PHD2 with PXLE-containing proteins, like NACA and p23, are critical for preventing erythrocytosis, particularly in high-altitude adapted populations like Tibetans.