The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 ac
Author: ["Daniel E. Foxler","Katherine S. Bridge","Victoria James","Thomas M. Webb","Maureen Mee","Sybil C. K. Wong","Yunfeng Feng","Dumitru Constantin-Teodosiu","Thorgunnur Eyfjord Petursdottir","Johannes Bjornsson","Sigurdur Ingvarsson","Peter J. Ratcliffe","Gregory D. Longmore","Tyson V. Sharp"]
Publication: Nature Cell Biology
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Abstract
Oxygen levels regulate the stability of the transcription factor HIF-1 through the action of prolyl hydroxylases and the VHL ubiquitin ligase. Sharp and colleagues now identify a protein complex in which the Ajuba LIM-domain protein LIMD1 brings together prolyl hydroxylases and VHL to ensure efficient degradation of HIF-1. There are three prolyl hydroxylases (PHD1, 2 and 3) that regulate the hypoxia-inducible factors (HIFs), the master transcriptional regulators that respond to changes in intracellular O2 tension1,2. In high O2 tension (normoxia) the PHDs hydroxylate two conserved proline residues on HIF-1α, which leads to binding of the von Hippel–Lindau (VHL) tumour suppressor, the recognition component of a ubiquitin–ligase complex, initiating HIF-1α ubiquitylation and degradation3,4,5,6. However, it is not known whether PHDs and VHL act separately to exert their enzymatic activities on HIF-1α or as a multiprotein complex. Here we show that the tumour suppressor protein LIMD1 (LIM domain-containing protein) acts as a molecular scaffold, simultaneously binding the PHDs and VHL, thereby assembling a PHD–LIMD1–VHL protein complex and creating an enzymatic niche that enables efficient degradation of HIF-1α. Depletion of endogenous LIMD1 increases HIF-1α levels and transcriptional activity in both normoxia and hypoxia. Conversely, LIMD1 expression downregulates HIF-1 transcriptional activity in a manner depending on PHD and 26S proteasome activities. LIMD1 family member proteins Ajuba and WTIP also bind to VHL and PHDs 1 and 3, indicating that these LIM domain-containing proteins represent a previously unrecognized group of hypoxic regulators.
Cite this article
Foxler, D., Bridge, K., James, V. et al. The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nat Cell Biol 14, 201–208 (2012). https://doi.org/10.1038/ncb2424
