Molecular glues that inhibit deubiquitylase activity and inflammatory signalling.
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All Authors
Chandler, F.
Reddy, PAN.
Bhutda, S.
Ross, RL.
Datta, A.
Walden, M.
Walker, K.
Di Donato, S.
Cassel, JA.
Prakesch, MA.
LTHT Author
Ross, Rebecca
Di Donato, Stefano
Del Galdo, Francesco
Di Donato, Stefano
Del Galdo, Francesco
LTHT Department
NIHR Leeds Biomedical Research Centre
Rheumatology
Rheumatology
Non Medic
Publication Date
2024
Item Type
Journal Article
Preprint
Preprint
Language
Subject
Subject Headings
Abstract
Deubiquitylases (DUBs) are crucial in cell signalling and are often regulated by interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signalling by cleaving K63-linked polyubiquitin chains on Type I interferon receptors (IFNAR1). As a Zn2+-dependent JAMM/MPN DUB, BRCC36 is challenging to target with selective inhibitors. We discovered first-in-class inhibitors, termed BRISC molecular glues (BLUEs), which stabilise a 16-subunit BRISC dimer in an autoinhibited conformation, blocking active sites and interactions with the targeting subunit SHMT2. 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 absent when using structure-guided, inhibitor-resistant BRISC mutants. Additionally, BLUEs increase IFNAR1 ubiquitylation and decrease IFNAR1 surface levels, offering a potential new 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.
Journal
BioRxiv : the Preprint Server for Biology