The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity.

Article Details

Citation

Foxler DE, Bridge KS, James V, Webb TM, Mee M, Wong SC, Feng Y, Constantin-Teodosiu D, Petursdottir TE, Bjornsson J, Ingvarsson S, Ratcliffe PJ, Longmore GD, Sharp TV

The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity.

Nat Cell Biol. 2012 Jan 29;14(2):201-8. doi: 10.1038/ncb2424.

PubMed ID
22286099 [ View in PubMed
]
Abstract

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 O(2) tension. In high O(2) tension (normoxia) the PHDs hydroxylate two conserved proline residues on HIF-1alpha, which leads to binding of the von Hippel-Lindau (VHL) tumour suppressor, the recognition component of a ubiquitin-ligase complex, initiating HIF-1alpha ubiquitylation and degradation. However, it is not known whether PHDs and VHL act separately to exert their enzymatic activities on HIF-1alpha 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-1alpha. Depletion of endogenous LIMD1 increases HIF-1alpha 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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Egl nine homolog 2Q96KS0Details
Egl nine homolog 1Q9GZT9Details
Egl nine homolog 3Q9H6Z9Details
Hypoxia-inducible factor 1-alphaQ16665Details