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bioRxiv · 10.1101/2024.01.29.577840

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

Wohlschlegel, J.·Mayank, A. K.·Pandey, V.·Li, L.·Jami-Alahmadi, Y.·Lien, K.·Kassem, A. M.
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Abstract

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 (SCFFBXL5), physically associates with VHL and promotes its ubiquitin-dependent degradation during hypoxia. The regulation of VHL protein stability by FBXL5 influences HIF1 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 HIF1-mediated cellular response to hypoxia and provides an additional layer of crosstalk between iron and oxygen homeostasis.

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Wohlschlegel, J., Mayank, A. K., Pandey, V., Li, L., Jami-Alahmadi, Y., Lien, K., Kassem, A. M.. 2024-01-30. SCF FBXL5 ubiquitin ligase regulates stability of von-Hippel Lindau protein and the HIF1α-dependent response to hypoxia. https://doi.org/10.1101/2024.01.29.577840

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