A new class of small molecular ‘glues’ selectively inhibit the BRISC deubiquitylase complex by stabilizing it in an inactive dimeric conformation. These compounds reduce inflammatory signaling by preventing deubiquitylation of an interferon receptor, and thereby offer a promising avenue for the treatment of type I interferon-driven diseases.
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References
Clague, M. J., Urbé, S. & Komander, D. Breaking the chains: deubiquitylating enzyme specificity begets function. Nat. Rev. Mol. Cell Biol. 20, 338–352 (2019). This comprehensive review summarizes the functional roles of DUBs.
Zheng, H. et al. A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses. Cell Rep. 5, 180–193 (2013). This article identifies the BRISC complex as a regulator of interferon signaling.
Zeqiraj, E. et al. Higher-order assembly of BRCC36-KIAA0157 is required for DUB activity and biological function. Mol. Cell 59, 970–983 (2015). This article describes the crystal structure of a minimally active DUB complex and the crucial role of allostery in BRCC36 function.
Walden, M. et al. Metabolic control of BRISC-SHMT2 assembly regulates immune signalling. Nature 570, 194–199 (2019). This article describes the cryo-EM structure of a full BRISC complex with its targeting partner SHMT2.
Schreiber, S. L. The rise of molecular glues. Cell 184, 3–9 (2021). This article explores the 30-year evolution of molecular glues, highlighting their transformative impact on drug development.
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E.Z. and F.C. used ChatGPT to help prepare their contribution to this Research Briefing.
This is a summary of: Chandler, F. et al. Molecular glues that inhibit deubiquitylase activity and inflammatory signaling. Nat. Struct. Mol. Biol. https://doi.org/10.1038/s41594-025-01517-5 (2025).
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Small-molecule glues selectively restrict deubiquitylase activity and inflammatory signaling. Nat Struct Mol Biol 32, 1592–1593 (2025). https://doi.org/10.1038/s41594-025-01518-4
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DOI: https://doi.org/10.1038/s41594-025-01518-4
