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去泛素化酶 Leon/USP5 与 Atg1/ULK1 相互作用并拮抗自噬。

The deubiquitinase Leon/USP5 interacts with Atg1/ULK1 and antagonizes autophagy.

机构信息

Institute of Biological Chemistry, Academia Sinica, Taipei, 115, Taiwan.

Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, 106, Taiwan.

出版信息

Cell Death Dis. 2023 Aug 22;14(8):540. doi: 10.1038/s41419-023-06062-x.

DOI:10.1038/s41419-023-06062-x
PMID:37607937
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10444890/
Abstract

Accumulating evidence has shown that the quality of proteins must be tightly monitored and controlled to maintain cellular proteostasis. Misfolded proteins and protein aggregates are targeted for degradation through the ubiquitin proteasome (UPS) and autophagy-lysosome systems. The ubiquitination and deubiquitinating enzymes (DUBs) have been reported to play pivotal roles in the regulation of the UPS system. However, the function of DUBs in the regulation of autophagy remain to be elucidated. In this study, we found that knockdown of Leon/USP5 caused a marked increase in the formation of autophagosomes and autophagic flux under well-fed conditions. Genetic analysis revealed that overexpression of Leon suppressed Atg1-induced cell death in Drosophila. Immunoblotting assays further showed a strong interaction between Leon/USP5 and the autophagy initiating kinase Atg1/ULK1. Depletion of Leon/USP5 led to increased levels of Atg1/ULK1. Our findings indicate that Leon/USP5 is an autophagic DUB that interacts with Atg1/ULK1, negatively regulating the autophagic process.

摘要

越来越多的证据表明，蛋白质的质量必须受到严格的监控和控制，以维持细胞内的蛋白质稳态。错误折叠的蛋白质和蛋白质聚集体通过泛素蛋白酶体 (UPS) 和自噬溶酶体系统被靶向降解。已报道泛素化和去泛素化酶 (DUBs) 在 UPS 系统的调节中发挥关键作用。然而，DUBs 在自噬调节中的功能仍有待阐明。在这项研究中，我们发现 Leon/USP5 的敲低会导致在营养充足的条件下自噬体和自噬流的形成明显增加。遗传分析显示，Leon 的过表达抑制了果蝇中 Atg1 诱导的细胞死亡。免疫印迹分析进一步显示 Leon/USP5 与自噬起始激酶 Atg1/ULK1 之间存在强烈的相互作用。Leon/USP5 的耗竭导致 Atg1/ULK1 的水平升高。我们的研究结果表明，Leon/USP5 是一种与 Atg1/ULK1 相互作用的自噬 DUB，负调控自噬过程。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/41d73be84cf0/41419_2023_6062_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/552cc3a18f70/41419_2023_6062_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/6ed115292699/41419_2023_6062_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/514c09f15692/41419_2023_6062_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/0a6bb89c3508/41419_2023_6062_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/dd0ec3dfade4/41419_2023_6062_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/41d73be84cf0/41419_2023_6062_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/552cc3a18f70/41419_2023_6062_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/1a5625490220/41419_2023_6062_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/6ed115292699/41419_2023_6062_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/514c09f15692/41419_2023_6062_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/0a6bb89c3508/41419_2023_6062_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/dd0ec3dfade4/41419_2023_6062_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bda0/10444890/41d73be84cf0/41419_2023_6062_Fig7_HTML.jpg

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