Molecular glues that inhibit deubiquitylase activity and inflammatory signaling
Deubiquitylases (DUBs) are crucial in cell signaling and are often regulated by interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signaling by cleaving K63-linked polyubiquitin chains on type I interferon receptors (IFNAR1). As a Zn<sup>2+</sup>-dependent JAMM/MPN (JAB1, MOV34, MPR1, Pad1 N-terminal) DUB, BRCC36 is challenging to target with selective inhibitors. Here, we discover first-in-class inhibitors, termed BRISC molecular glues (BLUEs), which stabilize a 16-subunit human BRISC dimer in an autoinhibited conformation, blocking active sites and interactions with the targeting subunit, serine hydroxymethyltransferase 2. This unique mode of action results in selective inhibition of BRISC over related complexes with the same catalytic subunit, splice variants and other JAMM/MPN DUBs. BLUE treatment reduced interferon-stimulated gene expression in cells containing wild-type BRISC and this effect was abolished when using structure-guided, inhibitor-resistant BRISC mutants. Additionally, BLUEs increase IFNAR1 ubiquitylation and decrease IFNAR1 surface levels, offering a potential strategy to mitigate type I interferon-mediated diseases. Our approach also provides a template for designing selective inhibitors of large protein complexes by promoting rather than blocking protein-protein interactions.
Authors
- Elton Zeqiraj (ORCID: https://orcid.org/0000-0003-0239-5926)
- Martina Foglizzo (ORCID: https://orcid.org/0000-0001-9132-4737)
- Joseph M. Salvino (ORCID: https://orcid.org/0000-0002-2184-5980)
- Alessandro Datti (ORCID: https://orcid.org/0000-0001-6824-7382)
- Francesca Chandler (ORCID: https://orcid.org/0000-0003-3465-7599)
- Miriam Walden (ORCID: https://orcid.org/0000-0002-0240-6106)
- Rima Al‐awar (ORCID: https://orcid.org/0000-0002-4185-055X)
- Antonio N. Calabrese (ORCID: https://orcid.org/0000-0003-2437-7761)
- Smita Bhutda (ORCID: https://orcid.org/0000-0003-1090-4639)
- Joel Cassel (ORCID: https://orcid.org/0000-0001-8465-8739)
- Arindam Datta (ORCID: https://orcid.org/0000-0002-0617-9908)
- Stefano Di Donato (ORCID: https://orcid.org/0000-0003-1256-0761)
- Michaël Prakesch (ORCID: https://orcid.org/0000-0003-2960-6471)
- Francesco Del Galdo (ORCID: https://orcid.org/0000-0002-8528-2283)
- James R. Ault (ORCID: https://orcid.org/0000-0002-5131-438X)
- Frank Sicheri (ORCID: https://orcid.org/0000-0002-9824-2117)
- Ahmed M. Aman (ORCID: https://orcid.org/0000-0002-0275-205X)
- Kieran Walker (ORCID: https://orcid.org/0000-0002-6694-2979)
- Dan Joseph Stein (ORCID: https://orcid.org/0000-0001-7218-7810)
- Adi Narayana Reddy Poli (ORCID: https://orcid.org/0000-0001-6288-9229)
- Roger A. Greenberg (ORCID: https://orcid.org/0000-0003-1326-8981)
- Lisa J. Campbell (ORCID: https://orcid.org/0000-0002-0452-0906)
- Rebecca L. Ross (ORCID: https://orcid.org/0000-0001-7750-4280)
- Lillie Bell
Institutions
- The Wistar Institute (US)
- Ontario Institute for Cancer Research (CA)
- University of Leeds (GB)
- University of Toronto (CA)
- Lunenfeld-Tanenbaum Research Institute (CA)
- University of Perugia (IT)
- Chapel Allerton Hospital (GB)
- Leeds Teaching Hospitals NHS Trust (GB)
- NIHR Leeds Musculoskeletal Biomedical Research Unit (GB)
- Penn Center for AIDS Research (US)
- Sinai Health System (CA)
- Institute of Structural and Molecular Biology (GB)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Structural & Molecular Biology
- Published
- 2025-03-17
- DOI
- https://doi.org/10.1038/s41594-025-01517-5
- Citations
- 5
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Medical Research Council
- Biotechnology and Biological Sciences Research Council