SCF FBXL5 ubiquitin ligase regulates stability of von-Hippel Lindau protein and the HIF1α-dependent response to hypoxia

The canonical response to changes in cellular oxygen levels consists of the ubiquitin-dependent degradation of hypoxia-inducible transcription factors (HIFs) in a prolyl hydroxylase (PHD) and von-Hippel Lindau-ElonginB-ElonginC (VHL-ElonginBC) E3 ubiquitin ligase complex-dependent manner. This regulated degradation event is oxygen-dependent and results in activation of a transcriptional program that mediates the cellular adaptation to changes in oxygen tension. Here, we show that a distinct Cullin RING ligase complex, SKP1-CUL1-FBXL5 (SCF FBXL5 ), physically associates with VHL and promotes its ubiquitin dependent degradation during hypoxia. The regulation of VHL protein stability by FBXL5 influences HIF1α expression levels and the transcriptional activation of downstream hypoxia-responsive target genes. This work identifies a novel mechanism for VHL regulation which contributes to the HIF1α-mediated cellular response to hypoxia and provides an additional layer of crosstalk between iron and oxygen homeostasis. ### Competing Interest Statement The authors have declared no competing interest.