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

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.

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Publication Details

Journal
Nature Communications
Published
2025-01-22
DOI
https://doi.org/10.1038/s41467-025-56336-5
Citations
1
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
0.81

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article

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

Marcin Drąg, Kiall F. Suazo, Euna Yoo, Ronald J. Holewinski et al.
1 citations
Nature Communications
Ubiquitin and proteasome pathways
0.81
article

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

Marcin Drąg, Kiall F. Suazo, Euna Yoo, Ronald J. Holewinski, Ye‐Jin Jung, Mo Yang, Þorkell Andrésson, Wioletta Rut, Anthony O. Omole, Griffin J. Davis, Hong‐Rae Kim
article en
1 citations

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.

Nature CommunicationsVol. 16(1)
Leidos (United States) (US), Wrocław University of Science and Technology (PL), National Institutes of Health (US), Korea University (KR), Frederick National Laboratory for Cancer Research (US), National Cancer Institute (US), Center for Cancer Research (US), Leidos Biomedical Research Inc. (United States), AGH University of Krakow (PL)
Frederick National Laboratory for Cancer Research, European Commission, Fundacja na rzecz Nauki Polskiej, National Institutes of Health, European Regional Development Fund, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 32%
Ubiquitin and proteasome pathways
0.81
DOIOpen Access PDFOpenAlex
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