A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF

TLDR

Mammalian cells sense oxygen via a conserved HIF pathway in which the HIF‑α subunit is hydroxylated on a proline residue, targeting it for degradation by a ubiquitin‑ligase complex under normoxic conditions. The study identified a conserved family of HIF prolyl‑hydroxylases (HPH) that mediate this hydroxylation, showed that HPH limits HIF accumulation in mammalian cells, and demonstrated that HPH knockdown in Drosophila elevates hypoxia‑inducible gene expression under normoxia, confirming HPH as essential for oxygen sensing.

Abstract

Mammalian cells respond to changes in oxygen availability through a conserved pathway that is regulated by the hypoxia-inducible factor (HIF). The alpha subunit of HIF is targeted for degradation under normoxic conditions by a ubiquitin-ligase complex that recognizes a hydroxylated proline residue in HIF. We identified a conserved family of HIF prolyl hydoxylase (HPH) enzymes that appear to be responsible for this posttranslational modification. In cultured mammalian cells, inappropriate accumulation of HIF caused by forced expression of the HIF-1alpha subunit under normoxic conditions was attenuated by coexpression of HPH. Suppression of HPH in cultured Drosophila melanogaster cells by RNA interference resulted in elevated expression of a hypoxia-inducible gene (LDH, encoding lactate dehydrogenase) under normoxic conditions. These findings indicate that HPH is an essential component of the pathway through which cells sense oxygen.