Scaffolding the regulation of hypoxia

Abstract

The expression of a subunit of the hypoxia-inducible factor (HIF) transcription factor, HIF1a, is suppressed in normoxia. This suppression is regulated by prolyl hydroxylases (PHDs), which hydroxylate HIF1a; this hydroxylation in turn recruits the von Hippel–Lindau (VHL) tumour suppressor, which is the recognition subunit of a ubiquitin ligase complex that targets HIF1a for proteasome-mediated degradation. Alterations to this process in tumour cells can cause inappropriate expression of HIF, which promotes tumour cell survival. It has remained unclear whether PHDs and the VHL complex act separately or in a macrocomplex. Foxler and colleagues show that LIM domain-containing (LIMD) proteins bind to both VHL and PHDs to function as a macrocomplex scaffold. Importantly, depletion of LIMD1 increased HIF1a levels in normoxia and hypoxia. Therefore, it will be interesting to investigate LIMD family-mediated regulation of responses to hypoxia in tumours.