title: Aggregation dynamics and identification of aggregation-prone mutants of the von Hippel-Lindau tumor suppressor protein.
abstract: Quality control mechanisms promote aggregation and degradation of misfolded proteins. In budding yeast, the human von Hippel-Lindau protein (pVHL, officially known as VHL) is misfolded and forms aggregates. Here, we investigated the aggregation of three pVHL isoforms (pVHL213, pVHL160, pVHL172) in fission yeast. The full-length pVHL213 isoform aggregates in highly dynamic small puncta and in large spherical inclusions, either close to the nucleus or to the cell ends. The large inclusions contain the yeast Hsp104 chaperone. Aggregate clearance is regulated by proteasomal degradation. The pVHL160 isoform forms dense foci and large irregularly shaped aggregates. In silico, prediction of pVHL aggregation propensity identified a key aggregation-promoting region within exon 2. Consistently, the pVHL172 isoform, which lacks exon 2, formed rare reduced inclusions. We studied the aggregation propensity of pVHL variants harbouring missense mutations found in kidney carcinomas. We show that the P86L mutation stimulated small aggregate formation, the P146A mutation increased large inclusion formation, whereas the I151S mutant destabilized pVHL. The prefoldin subunit Pac10 (the human homolog VBP-1 binds to pVHL) is required for pVHL stability. Reduction of soluble functional pVHL might be crucial in VHL-related diseases.
authors.affiliation: CNRS, UMR 6290 IGDR, Université Rennes 1, BIOSIT, Molecular Bases of Tumorigenesis: VHL Disease Team, 35043 Rennes cedex, France xavier.le-goff@univ-rennes1.fr.
authors.forename: Xavier
authors.identifier: 0000-0002-5297-2421
authors.initials: X
authors.lastname: Le Goff
authors.affiliation: CNRS, UMR 6290 IGDR, Université Rennes 1, BIOSIT, Molecular Bases of Tumorigenesis: VHL Disease Team, 35043 Rennes cedex, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Chesnel
authors.affiliation: CNRS, UMR 6290 IGDR, Université Rennes 1, BIOSIT, Molecular Bases of Tumorigenesis: VHL Disease Team, 35043 Rennes cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delalande
authors.affiliation: CNRS, UMR 6290 IGDR, Université Rennes 1, BIOSIT, Molecular Bases of Tumorigenesis: VHL Disease Team, 35043 Rennes cedex, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Couturier
authors.affiliation: CNRS, UMR 6290 IGDR, Université Rennes 1, BIOSIT, Molecular Bases of Tumorigenesis: VHL Disease Team, 35043 Rennes cedex, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dréano
authors.affiliation: CNRS, UMR 6290 IGDR, Université Rennes 1, BIOSIT, Molecular Bases of Tumorigenesis: VHL Disease Team, 35043 Rennes cedex, France.
authors.forename: Cathy
authors.initials: C
authors.lastname: Le Goff
authors.affiliation: CNRS, UMR 6290 IGDR, Université Rennes 1, BIOSIT, Molecular Bases of Tumorigenesis: VHL Disease Team, 35043 Rennes cedex, France CHU Rennes, service de néphrologie, 35000 Rennes, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Vigneau
authors.affiliation: CNRS, UMR 6290 IGDR, Université Rennes 1, BIOSIT, Molecular Bases of Tumorigenesis: VHL Disease Team, 35043 Rennes cedex, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Arlot-Bonnemains
mesh_terms: D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation; D066263:Protein Aggregation, Pathological / Q000235:genetics*; D017510:Protein Folding; D020033:Protein Isoforms; D012568:Schizosaccharomyces / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D018832:Molecular Chaperones; C000621668:Pac10 protein, S pombe; D020033:Protein Isoforms; D029702:Schizosaccharomyces pombe Proteins; D025521:Tumor Suppressor Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: Protein aggregation; Schizosaccharomyces pombe; VHL; ccRCC