Mutations in the von Hippel−Lindau tumor suppressor (VHL) gene cause a inherited cancer disorder, the VHL syndrome. Many mutations in the VHL gene have been described in patients with VHL disease, but few have been functionally characterised. In budding yeast, the human VHL protein (VHL, hereafter referred to as pVHL) is misfolded and forms aggregates under normal growth conditions and now (p. ), Xavier Le Goff, Yannick Arlot-Bonnemains and colleagues explore the aggregation properties of the three pVHL isoforms (pVHL213, pVHL160, pVHL172) in the fission yeast Schizosaccharomyces pombe. In this work, the authors promote protein aggregation by overexpressing all three pVHL isoforms. They show that full-length pVHL213 can form two distinct aggregates: small, dynamic aggregates and large, slow-moving inclusions. The pVHL172 isoform forms small dynamic aggregates and intermediate-sized inclusions, whereas the pVHL160 isoform forms dense foci and large, irregularly shaped aggregates. The authors then identify three pVHL tumorigenic mutants and examine their aggregation propensities. They find that the P86L mutation promotes the formation of the small, dynamic aggregates, and the P146A mutation increases the size of the large, slow-moving inclusions. The I151S mutation, however, which is located in the same aggregation-prone region as P146, decreases large inclusion formation. Finally, the authors show that the prefoldin subunit Pac10 is required for the formation of the large inclusions. This study advances our currently knowledge of the key factors that control the folding and aggregation of the VHL protein.
