Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein

Nat Genet. 2003 Nov;35(3):229-37. doi: 10.1038/ng1254. Epub 2003 Oct 12.

Abstract

von Hippel-Lindau (VHL) gene inactivation occurs in von Hippel-Lindau (VHL) disease. The protein pVHL functions in a multi-subunit E3 ubiquitin ligase that targets the hypoxia-inducible transcription factor Hif1 alpha for proteasomal degradation during normoxia. We establish that pVHL binds to Tat-binding protein-1 (TBP-1), a component of the 19S regulatory complex of the proteasome. TBP-1 associates with the beta-domain of pVHL and complexes with pVHL and Hif1 alpha in vivo. Overexpression of TBP-1 promotes degradation of Hif1 alpha in a pVHL-dependent manner that requires the ATPase domain of TBP-1. Blockade of TBP-1 expression by small interfering RNA (siRNA) causes prolonged degradation kinetics of Hif1 alpha. Several distinct mutations in exon 2 of VHL disrupt binding of pVHL to TBP-1. A pVHL mutant containing a P154L substitution coimmunoprecipitates with Hif1 alpha, but not TBP-1, and does not promote degradation of Hif1 alpha. Thus, the ability of pVHL to degrade Hif1 alpha depends in part on its interaction with TBP-1 and suggests a new mechanism for Hif1 alpha stabilization in some pVHL-deficient tumors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Base Sequence
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Humans
  • Hydrolysis
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Molecular Sequence Data
  • Peptide Hydrolases / metabolism*
  • Proteasome Endopeptidase Complex*
  • Protein Binding
  • RNA, Small Interfering
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / physiology*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitin-Protein Ligases / physiology*
  • Von Hippel-Lindau Tumor Suppressor Protein

Substances

  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Peptide Hydrolases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease
  • ATPases Associated with Diverse Cellular Activities
  • PSMC3 protein, human
  • VHL protein, human

Associated data

  • GENBANK/M34079
  • GENBANK/X65324
  • RefSeq/NM_008948