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.

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., 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

• 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
• DOI: https://doi.org/10.1038/ncb2424
• Public URL: https://nottingham-repository.worktribe.com/output/1376910
• Publisher URL: https://www.nature.com/articles/ncb2424