Chemical tools to define and manipulate interferon-inducible Ubl protease USP18

Griffin J. Davis, Anthony O. Omole, Yejin Jung, Wioletta Rut, Ronald Holewinski, Kiall F. Suazo, Hong-Rae Kim, Mo Yang, Thorkell Andresson, Marcin Drag and Euna Yoo ()
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Griffin J. Davis: National Cancer Institute, National Institutes of Health
Anthony O. Omole: National Cancer Institute, National Institutes of Health
Yejin Jung: National Cancer Institute, National Institutes of Health
Wioletta Rut: Wroclaw University of Science and Technology
Ronald Holewinski: Frederick National Laboratory for Cancer Research, Leidos Biomedical Research
Kiall F. Suazo: Frederick National Laboratory for Cancer Research, Leidos Biomedical Research
Hong-Rae Kim: National Cancer Institute, National Institutes of Health
Mo Yang: National Cancer Institute, National Institutes of Health
Thorkell Andresson: Frederick National Laboratory for Cancer Research, Leidos Biomedical Research
Marcin Drag: Wroclaw University of Science and Technology
Euna Yoo: National Cancer Institute, National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Ubiquitin-specific protease 18 (USP18) is a multifunctional cysteine protease primarily responsible for deconjugating the interferon-inducible ubiquitin-like modifier ISG15 from protein substrates. Here, we report the design and synthesis of activity-based probes (ABPs) that incorporate unnatural amino acids into the C-terminal tail of ISG15, enabling the selective detection of USP18 activity over other ISG15 cross-reactive deubiquitinases (DUBs) such as USP5 and USP14. Combined with a ubiquitin-based DUB ABP, the USP18 ABP is employed in a chemoproteomics screening platform to identify and assess inhibitors of DUBs including USP18. We further demonstrate that USP18 ABPs can be utilized to profile differential activities of USP18 in lung cancer cell lines, providing a strategy that will help define the activity-related landscape of USP18 in different disease states and unravel important (de)ISGylation-dependent biological processes.

Date: 2025
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DOI: 10.1038/s41467-025-56336-5

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