Chemical tools to define and manipulate interferon-inducible Ubl protease USP18
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 unn...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56336-5 |
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| author | Griffin J. Davis Anthony O. Omole Yejin Jung Wioletta Rut Ronald Holewinski Kiall F. Suazo Hong-Rae Kim Mo Yang Thorkell Andresson Marcin Drag Euna Yoo |
| author_facet | Griffin J. Davis Anthony O. Omole Yejin Jung Wioletta Rut Ronald Holewinski Kiall F. Suazo Hong-Rae Kim Mo Yang Thorkell Andresson Marcin Drag Euna Yoo |
| author_sort | Griffin J. Davis |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-150b00e079594d35a3975382116fcc85 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-150b00e079594d35a3975382116fcc852025-01-26T12:41:27ZengNature PortfolioNature Communications2041-17232025-01-0116111710.1038/s41467-025-56336-5Chemical tools to define and manipulate interferon-inducible Ubl protease USP18Griffin J. Davis0Anthony O. Omole1Yejin Jung2Wioletta Rut3Ronald Holewinski4Kiall F. Suazo5Hong-Rae Kim6Mo Yang7Thorkell Andresson8Marcin Drag9Euna Yoo10Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of HealthChemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of HealthChemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of HealthDepartment of Chemical Biology and Bioimaging, Wroclaw University of Science and TechnologyProtein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical ResearchProtein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical ResearchChemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of HealthChemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of HealthProtein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical ResearchDepartment of Chemical Biology and Bioimaging, Wroclaw University of Science and TechnologyChemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of HealthAbstract 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.https://doi.org/10.1038/s41467-025-56336-5 |
| spellingShingle | Griffin J. Davis Anthony O. Omole Yejin Jung Wioletta Rut Ronald Holewinski Kiall F. Suazo Hong-Rae Kim Mo Yang Thorkell Andresson Marcin Drag Euna Yoo Chemical tools to define and manipulate interferon-inducible Ubl protease USP18 Nature Communications |
| title | Chemical tools to define and manipulate interferon-inducible Ubl protease USP18 |
| title_full | Chemical tools to define and manipulate interferon-inducible Ubl protease USP18 |
| title_fullStr | Chemical tools to define and manipulate interferon-inducible Ubl protease USP18 |
| title_full_unstemmed | Chemical tools to define and manipulate interferon-inducible Ubl protease USP18 |
| title_short | Chemical tools to define and manipulate interferon-inducible Ubl protease USP18 |
| title_sort | chemical tools to define and manipulate interferon inducible ubl protease usp18 |
| url | https://doi.org/10.1038/s41467-025-56336-5 |
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