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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.


Daniel E. Foxler

Katherine S. Bridge

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


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.


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.

Journal Article Type Article
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
Public URL
Publisher URL