Daniel E. Foxler
The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity
Foxler, Daniel E.; Bridge, Katherine S.; James, Victoria; Webb, Thomas M.; Mee, Maureen; Wong, Sybil C. K.; Feng, Yunfeng; Constantin-Teodosiu, Dumitru; Petursdottir, Thorgunnur Eyfjord; Bjornsson, Johannes; Ingvarsson, Sigurdur; Ratcliffe, Peter J.; Longmore, Gregory D.; Sharp, Tyson V.
Authors
Katherine S. Bridge
VICTORIA JAMES Victoria.James@nottingham.ac.uk
Associate Professor
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
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 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.
Citation
Foxler, D. E., Bridge, K. S., James, V., Webb, T. M., Mee, M., Wong, S. C. K., …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
Journal Article Type | Article |
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Acceptance Date | Dec 16, 2011 |
Online Publication Date | Jan 29, 2012 |
Publication Date | 2012-02 |
Deposit Date | Dec 6, 2018 |
Journal | Nature Cell Biology |
Print ISSN | 1465-7392 |
Electronic ISSN | 1476-4679 |
Publisher | Nature Publishing Group |
Peer Reviewed | Peer Reviewed |
Volume | 14 |
Issue | 2 |
Pages | 201-208 |
DOI | https://doi.org/10.1038/ncb2424 |
Public URL | https://nottingham-repository.worktribe.com/output/1376910 |
Publisher URL | https://www.nature.com/articles/ncb2424 |