An adaptive stress response that confers cellular resilience to decreased ubiquitination.
An adaptive stress response that confers cellular resilience to decreased ubiquitination.
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DOI：
10.1038/s41467-023-43262-7
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发表时间：
2023-11-14
影响因子：
16.6
通讯作者：
Demontis, Fabio
中科院分区：
文献类型：
--
作者：
Hunt, Liam C.;Pagala, Vishwajeeth;Stephan, Anna;Xie, Boer;Kodali, Kiran;Kavdia, Kanisha;Wang, Yong-Dong;Shirinifard, Abbas;Curley, Michelle;Graca, Flavia A.;Fu, Yingxue;Poudel, Suresh;Li, Yuxin;Wang, Xusheng;Tan, Haiyan;Peng, Junmin;Demontis, Fabio
泛素化是由E1酶UBA 1启动的翻译后修饰，其将泛素转移到~35个E2泛素缀合酶。虽然UBA 1损失是细胞致命的，但仍不清楚UBA 1活性的部分降低是如何忍受的。在这里，我们利用深度覆盖质谱来定义E1-E2相互作用组，并确定在人类细胞中通过敲低UBA 1和每个E2来调节的蛋白质。这些分析定义了UBA 1/E2敏感蛋白质组和蛋白质调节中的E2特异性。有趣的是，过氧化物酶体和其他细胞器的深刻适应是由泛素化的减少引发的。虽然货物受体PEX 5依赖于其单泛素化结合过氧化物酶体蛋白，并将其导入过氧化物酶体，我们发现UBA 1/E2敲低诱导PEX 5对接到过氧化物酶体膜所需的其他PEX蛋白的补偿性上调。总之，这项研究定义了一个稳态机制，维持过氧化物酶体蛋白进口细胞的泛素化能力下降。Hunt等人鉴定了人类细胞中每种E2泛素缀合酶受RNAi调节的蛋白质组。通过分析UBA 1/E2敏感蛋白质组，他们报告了一种适应性应激反应，该反应在泛素化能力降低的细胞中保留了过氧化物酶体蛋白的输入。
Ubiquitination is a post-translational modification initiated by the E1 enzyme UBA1, which transfers ubiquitin to ~35 E2 ubiquitin-conjugating enzymes. While UBA1 loss is cell lethal, it remains unknown how partial reduction in UBA1 activity is endured. Here, we utilize deep-coverage mass spectrometry to define the E1-E2 interactome and to determine the proteins that are modulated by knockdown of UBA1 and of each E2 in human cells. These analyses define the UBA1/E2-sensitive proteome and the E2 specificity in protein modulation. Interestingly, profound adaptations in peroxisomes and other organelles are triggered by decreased ubiquitination. While the cargo receptor PEX5 depends on its mono-ubiquitination for binding to peroxisomal proteins and importing them into peroxisomes, we find that UBA1/E2 knockdown induces the compensatory upregulation of other PEX proteins necessary for PEX5 docking to the peroxisomal membrane. Altogether, this study defines a homeostatic mechanism that sustains peroxisomal protein import in cells with decreased ubiquitination capacity. Hunt et al. identify the protein sets that are modulated by RNAi for each E2 ubiquitin-conjugating enzyme in human cells. By analyzing the UBA1/E2-sensitive proteome, they report an adaptive stress response that preserves peroxisomal protein import in cells with decreased ubiquitination capacity.
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