Hypoxia-inducible factors (HIFs) are central regulators of the cellular and systemic response to changes in oxygen partial pressure. HIFa subunits are constitutively expressed but rapidly degraded by the ubiquitin proteasome pathway under normoxic conditions. Prerequisite for this oxygen-dependent degradation is hydroxylation of specific prolyl residues in HIFa subunits by prolyl-4-hydroxylase domain (PHD) enzymes. Because PHDs are absolutely dependent on molecular di-oxygen as co-substrate, they serve as cellular oxygen sensors and provide a direct link between tissue oxygenation and the stability of HIFa subunits.

We identified the FK506-binding protein 38 (FKBP38), a peptidyl prolyl cis/trans isomerase (PPIase), as specific PHD2 interactor. Stable downregulation of FKBP38 by RNA interference (RNAi) resulted in enhanced hydroxylation activity and increased PHD2 protein levels. These effects in FKBP38

RNAi cell clones were rescued by overexpression of either FKBP38 or a FKBP38 PPIase domain deletion mutant, but not by expression of FKBP38 mutant in which the transmembrane domain was deleted. These data suggest that PHD2 protein abundance is regulated by FKBP38-dependent subcellular localization.