Protist oxygen-sensing and the role of prolyl hydroxylase-regulation of E3(SCF) ubiquitin ligases
A primary mechanism for sensing O2 in animals involves the O2-dependent prolyl hydroxylase PHD2, which generates a degron on the transcription co-factor HIF-α. In protists, its apparent evolutionary predecessor, PhyA, is dedicated to the modification of Skp1. Skp1 is a subunit of the E3(SCF) family of ubiquitin ligases whose impact on the proteome is mediated by multiple F-box protein (FBP) substrate receptors. In the social amoeba Dictyostelium, genetic manipulations of PhyA and Skp1 levels lead to reciprocal effects on an O2-dependent developmental transition. PhyA is also required for fitness and virulence of the pathogen Toxoplasma gondii. The effects of PhyA depend on subsequent glycosylation of the target hydroxyproline, which inhibits sequestration of Skp1 by homodimerization and promotes interaction with select FBPs. Action via protein degradation is indicated by compensatory effects of proteasomal inhibition. Significance is indicated by evidence for Skp1 modification throughout protists and occurrence of non-modifiable Skp1 paralogs. This review critically evaluates evidence for an original role of prolyl hydroxylases to mediate protist O2-sensing via proteome-wide degradation that preceded its transition to HIF-α dependent transcriptional regulation in animals.
Donovan A Cantrell, Ira J Blader, Christopher M West. Biochim Biophys Acta Gen Subj. 2026 Mar 6:130928. doi: 10.1016/j.bbagen.2026.130928.