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 was 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.

von Hippel-Lindau蛋白pVHL功能的丧失会促进VHL疾病，包括散发性和遗传性透明细胞肾细胞癌（ccRCC）。控制pVHL功能和调节的机制（包括折叠和稳定性）仍然难以捉摸。在这里，我们已经在pVHL相互作用物的筛选中鉴定了保守的伴侣蛋白前折叠复合物。前折叠蛋白复合物将非天然蛋白递送至伴侣蛋白T-复合物蛋白-1-环（TRiC）或含有TCP-1的胞质伴侣蛋白（CCT），以协助新合成的多肽折叠。在人细胞中证实了pVHL-前折叠蛋白的相互作用，并且前折叠蛋白的敲低降低了pVHL表达水平。此外，当在粟酒裂殖酵母中表达pVHL时，所有prefoldin突变体均促进了其聚集。我们在preon2-exon3结编码区域绘制了prefoldin与pVHL的相互作用。在携带VHL突变的ccRCC患者中，低水平的PFDN3前折叠蛋白亚基与存活率低有关。我们的结果将前折叠蛋白复合物与pVHL折叠联系起来，这可能影响VHL疾病的进展。