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

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.

Pubmed ID: 22286099

Authors

  • 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

Journal

Nature cell biology

Publication Data

February 2, 2012

Associated Grants

  • Agency: Biotechnology and Biological Sciences Research Council, Id: BB/F006470/1
  • Agency: Biotechnology and Biological Sciences Research Council, Id: BB/I007571/1

Mesh Terms

  • Cell Hypoxia
  • Cell Line, Tumor
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Hydroxylation
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Immunoblotting
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • Models, Biological
  • Polyubiquitin
  • Procollagen-Proline Dioxygenase
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • RNA Interference
  • Transfection
  • Two-Hybrid System Techniques
  • Ubiquitination
  • Von Hippel-Lindau Tumor Suppressor Protein