英国剑桥大学David C. Rubinsztein团队近期取得重要工作进展，他们研究提出，核蛋白酶体在自噬受损过程中能缓冲细胞质蛋白。相关研究成果2024年8月29日在线发表于《自然—细胞生物学》杂志上。

据介绍，自噬是一种保守的途径，细胞质内容物被自噬体吞噬，然后与溶酶体融合，使其降解。核心自噬基因的突变会导致神经系统疾病，自噬缺陷见于帕金森病和亨廷顿氏病等神经退行性疾病。

研究人员试图通过使用酵母筛选的可用数据，在自噬缺失的人类细胞中寻找负面的遗传相互作用，如合成致死性，来了解自噬紊乱细胞容易受到的细胞通路扰动。

这一研究表明，蛋白酶体和核孔复合物成分的损失会导致协同的存活率变化，类似于自噬缺失细胞中的合成适应度损失。这可以归因于在自噬缺陷期间蛋白质的细胞质到核的运输，以及随后这些以前的细胞质蛋白质被核蛋白酶体降解。由于亨廷顿氏病中的自噬和细胞质到核的运输都有缺陷，因此这些细胞更容易受到这些合成相互作用引起的蛋白质稳态紊乱的干扰。

附：英文原文

Title: Nuclear proteasomes buffer cytoplasmic proteins during autophagy compromise

Author: Park, So Jung, Son, Sung Min, Barbosa, Antonio Daniel, Wrobel, Lidia, Stamatakou, Eleanna, Squitieri, Ferdinando, Balmus, Gabriel, Rubinsztein, David C.

Issue&Volume: 2024-08-29

Abstract: Autophagy is a conserved pathway where cytoplasmic contents are engulfed by autophagosomes, which then fuse with lysosomes enabling their degradation. Mutations in core autophagy genes cause neurological conditions, and autophagy defects are seen in neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease. Thus, we have sought to understand the cellular pathway perturbations that autophagy-perturbed cells are vulnerable to by seeking negative genetic interactions such as synthetic lethality in autophagy-null human cells using available data from yeast screens. These revealed that loss of proteasome and nuclear pore complex components cause synergistic viability changes akin to synthetic fitness loss in autophagy-null cells. This can be attributed to the cytoplasm-to-nuclear transport of proteins during autophagy deficiency and subsequent degradation of these erstwhile cytoplasmic proteins by nuclear proteasomes. As both autophagy and cytoplasm-to-nuclear transport are defective in Huntington’s disease, such cells are more vulnerable to perturbations of proteostasis due to these synthetic interactions.

DOI: 10.1038/s41556-024-01488-7

Source: https://www.nature.com/articles/s41556-024-01488-7