The prefoldin complex stabilizes the von Hippel-Lindau protein against aggregation and degradation

PLoS Genet. 2020 Nov 2;16(11):e1009183. doi: 10.1371/journal.pgen.1009183. eCollection 2020 Nov.

Abstract

Loss of von Hippel-Lindau protein pVHL function promotes VHL diseases, including sporadic and inherited clear cell Renal Cell Carcinoma (ccRCC). Mechanisms controlling pVHL function and regulation, including folding and stability, remain elusive. Here, we have identified the conserved cochaperone prefoldin complex in a screen for pVHL interactors. The prefoldin complex delivers non-native proteins to the chaperonin T-complex-protein-1-ring (TRiC) or Cytosolic Chaperonin containing TCP-1 (CCT) to assist folding of newly synthesized polypeptides. The pVHL-prefoldin interaction was confirmed in human cells and prefoldin knock-down reduced pVHL expression levels. Furthermore, when pVHL was expressed in Schizosaccharomyces pombe, all prefoldin mutants promoted its aggregation. We mapped the interaction of prefoldin with pVHL at the exon2-exon3 junction encoded region. Low levels of the PFDN3 prefoldin subunit were associated with poor survival in ccRCC patients harboring VHL mutations. Our results link the prefoldin complex with pVHL folding and this may impact VHL diseases progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chaperonin Containing TCP-1
  • Cytoskeletal Proteins / metabolism*
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Kaplan-Meier Estimate
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / mortality
  • Kidney Neoplasms / pathology
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Mutation
  • Protein Binding / genetics
  • Protein Folding
  • Proteolysis
  • Schizosaccharomyces
  • Schizosaccharomyces pombe Proteins / genetics
  • Schizosaccharomyces pombe Proteins / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*

Substances

  • Cytoskeletal Proteins
  • Molecular Chaperones
  • Schizosaccharomyces pombe Proteins
  • VBP1 protein, human
  • prefoldin
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Chaperonin Containing TCP-1
  • VHL protein, human

Grant support

Grants Ligue Contre le Cancer CD35 2014-2015-2016 (https://www.ligue-cancer.net/cd35/journal) to YAB. PH was supported by a "contrat doctoral d'établissement 2012–2015" from University of Rennes 1 and was the recipient of a "Young Researcher" fellowship DOC20150602688 from the Fondation ARC pour la Recherche sur le Cancer (https://www.fondation-arc.org).