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- Title
An adaptive stress response that confers cellular resilience to decreased ubiquitination.
- Authors
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
- Abstract
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.
- Subjects
UBIQUITINATION; UBIQUITIN-conjugating enzymes; POST-translational modification; CARRIER proteins; UBIQUITIN; PEROXISOMES
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-43262-7