荷兰格罗宁根大学Fulvio Reggiori小组取得一项新突破。他们研制了基于伴侣-蛋白酶体的裂解机制对于聚合是必不可少的。该研究于2025年8月27日发表于国际一流学术期刊《自然—细胞生物学》杂志上。

在这里，研究小组揭示了在自噬清除各种类型的无定形聚集体之前需要碎片化。这种断裂需要19S蛋白酶体调节颗粒和DNAJB6-HSP70-HSP110伴侣模块。这两个参与者对于聚集体的压实也是必不可少的，这种压实导致选择性自噬受体的聚集，从而启动聚集体的自噬去除。该课题组研究人员还发现，同样的玩家延缓了与疾病相关的亨廷顿舞蹈症的形成。本研究为19S调控颗粒和DNAJB6-HSP70-HSP110模块赋予了一种新的功能，并揭示了聚合需要一个零碎的过程，与蛋白质病变相关。

据介绍，蛋白质质量控制中的扰动导致错误折叠蛋白质和蛋白质聚集体的积累，这可能损害健康和寿命。消除蛋白质聚集的一个关键机制是聚集性，这是一种选择性的自噬。

附：英文原文

Title: A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy

Author: Mauthe, Mario, van de Beek, Nicole, Mari, Muriel, Korsten, Giel, Nobari, Parisa, Castelino, Kennith B., de Mattos, Eduardo P., Ouhida, Ibtisam, Dijkstra, Jesse L., Schipper-Krom, Sabine, de la Ballina, Laura R., Mueller, Monja R., Simonsen, Anne, Hipp, Mark S., Kapitein, Lukas C., Kampinga, Harm H., Reggiori, Fulvio

Issue&Volume: 2025-08-27

Abstract: Perturbations in protein quality control lead to the accumulation of misfolded proteins and protein aggregates, which can compromise health and lifespan. One key mechanism eliminating protein aggregates is aggrephagy, a selective type of autophagy. Here we reveal that fragmentation is required before autophagic clearance of various types of amorphous aggregates. This fragmentation requires both the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module. These two players are also essential for aggregate compaction that leads to the clustering of the selective autophagy receptors, which initiates the autophagic removal of the aggregates. We also found that the same players delay the formation of disease-associated huntingtin inclusions. This study assigns a novel function to the 19S regulatory particle and the DNAJB6-HSP70-HSP110 module, and uncovers that aggrephagy entails a piecemeal process, with relevance for proteinopathies.

DOI: 10.1038/s41556-025-01747-1

Source: https://www.nature.com/articles/s41556-025-01747-1