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

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

Research output: Contribution to journalArticle

49 Scopus citations

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-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 degradation. 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.

Original languageEnglish
Pages (from-to)201-208
Number of pages8
JournalNature Cell Biology
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2012
Externally publishedYes

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    Foxler, D. E., Bridge, K. S., James, V., Webb, T. M., Mee, M., Wong, S. C. K., Feng, Y., Constantin-Teodosiu, D., Petursdottir, T. E., Bjornsson, J., Ingvarsson, S., Ratcliffe, P. J., Longmore, G. D., & Sharp, T. V. (2012). The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nature Cell Biology, 14(2), 201-208. https://doi.org/10.1038/ncb2424