美国耶鲁大学Pietro De Camilli团队的最新研究揭示了桥状脂质转运蛋白VPS13C/PARK23介导溶酶体损伤后的ER溶酶体接触。2025年4月10日出版的《自然—细胞生物学》发表了这项成果。

在这里，课题组发现VPS13C，一种桥状脂质转运蛋白和帕金森病基因，是溶酶体应激或损伤的传感器。在溶酶体膜受到扰动后，VPS13C迅速从细胞质转移到溶酶体表面，并将溶酶体膜与内质网连接。这种招募依赖于Rab7，并且需要在受损的溶酶体表面发出信号，释放VPS13C的抑制状态，从而阻碍其VAB结构域进入溶酶体结合的Rab7。尽管另一种帕金森病蛋白LRRK2也被招募到应激或受损的溶酶体中，但其招募发生在更晚的阶段，并且通过不同的机制。考虑到VPS13蛋白在脂质运输中的作用，这些发现表明，通过VPS13C将脂质传递到溶酶体是溶酶体损伤的早期保护性反应的一部分。

据悉，基于遗传学研究，溶酶体功能障碍被认为在帕金森病中起发病作用。

附：英文原文

Title: The bridge-like lipid transport protein VPS13C/PARK23 mediates ER–lysosome contacts following lysosome damage

Author: Wang, Xinbo, Xu, Peng, Bentley-DeSousa, Amanda, Hancock-Cerutti, William, Cai, Shujun, Johnson, Benjamin T., Tonelli, Francesca, Shao, Lin, Talaia, Gabriel, Alessi, Dario R., Ferguson, Shawn M., De Camilli, Pietro

Issue&Volume: 2025-04-10

Abstract: Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson’s disease. Here we show that VPS13C, a bridge-like lipid-transport protein and a Parkinson’s disease gene, is a sensor of lysosome stress or damage. Following lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged lysosome surface that releases an inhibited state of VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. Although another Parkinson’s disease protein, LRRK2, is also recruited to stressed or damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the role of VPS13 proteins in bulk lipid transport, these findings suggest that lipid delivery to lysosomes by VPS13C is part of an early protective response to lysosome damage.

DOI: 10.1038/s41556-025-01653-6

Source: https://www.nature.com/articles/s41556-025-01653-6