An adaptive stress response that confers cellular resilience to decreased ubiquitination

Liam C. Hunt, Vishwajeeth Pagala, Anna Stephan, Boer Xie, Kiran Kodali, Kanisha Kavdia, Yong-Dong Wang, Abbas Shirinifard, Michelle Curley, Flavia A. Graca, Yingxue Fu, Suresh Poudel, Yuxin Li, Xusheng Wang, Haiyan Tan, Junmin Peng and Fabio Demontis ()
Additional contact information
Liam C. Hunt: St. Jude Children’s Research Hospital
Vishwajeeth Pagala: St. Jude Children’s Research Hospital
Anna Stephan: St. Jude Children’s Research Hospital
Boer Xie: St. Jude Children’s Research Hospital
Kiran Kodali: St. Jude Children’s Research Hospital
Kanisha Kavdia: St. Jude Children’s Research Hospital
Yong-Dong Wang: St. Jude Children’s Research Hospital
Abbas Shirinifard: St. Jude Children’s Research Hospital
Michelle Curley: St. Jude Children’s Research Hospital
Flavia A. Graca: St. Jude Children’s Research Hospital
Yingxue Fu: St. Jude Children’s Research Hospital
Suresh Poudel: St. Jude Children’s Research Hospital
Yuxin Li: St. Jude Children’s Research Hospital
Xusheng Wang: St. Jude Children’s Research Hospital
Haiyan Tan: St. Jude Children’s Research Hospital
Junmin Peng: St. Jude Children’s Research Hospital
Fabio Demontis: St. Jude Children’s Research Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43262-7

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