Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes)-UMR 6290, France.
Department of Molecular Biology, Medical Biochemistry and Pathology; Université Laval, Québec City, Québec, Canada.
PLoS Genet. 2020 Nov 2;16(11):e1009183. doi: 10.1371/journal.pgen.1009183. eCollection 2020 Nov.
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.
抑癌基因 VHL 蛋白功能丧失会促进 VHL 疾病的发生，包括散发性和遗传性透明细胞肾细胞癌（ccRCC）。控制 VHL 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，我们在筛选 VHL 相互作用蛋白时发现了保守的共伴侣前折叠复合物。前折叠复合物将非天然蛋白质递送到伴侣蛋白 T 复合物蛋白 1 环（TRiC）或胞质伴侣蛋白 1 包含 TCP-1（CCT），以协助新合成多肽的折叠。在人细胞中证实了 VHL-前折叠复合物的相互作用，并且前折叠复合物的敲低降低了 VHL 的表达水平。此外，当 VHL 在酿酒酵母中表达时，所有前折叠复合物突变体都促进了其聚集。我们将前折叠复合物与 VHL 的相互作用定位在编码区域的外显子 2-外显子 3 交界处。在携带 VHL 突变的 ccRCC 患者中，低水平的前折叠复合物 PFDN3 亚基与较差的生存相关。我们的结果将前折叠复合物与 VHL 的折叠联系起来，这可能会影响 VHL 疾病的进展。
