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.
Access through your institution
Buy or subscribe
This is a preview of subscription content, access via your institution
Access options
Access through your institution
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Learn more
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Learn more
Buy this article
Purchase on SpringerLink
Instant access to full article PDF
Buy now
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Log in
Learn about institutional subscriptions
Read our FAQs
Contact customer support
Fig. 1: BRISC structure in complex with molecular glues.
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.
ArticleCASPubMedGoogle Scholar
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.
ArticleCASPubMedGoogle Scholar
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.
ArticleCASPubMedPubMed CentralGoogle Scholar
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.
ArticleCASPubMedPubMed CentralGoogle Scholar
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.
ArticleCASPubMedGoogle Scholar
Download references
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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).
Rights and permissions
Reprints and permissions
About this article
Check for updates. Verify currency and authenticity via CrossMark
Cite this article
Small-molecule glues selectively restrict deubiquitylase activity and inflammatory signaling. Nat Struct Mol Biol (2025). https://doi.org/10.1038/s41594-025-01518-4
Download citation
Published:25 March 2025
DOI:https://doi.org/10.1038/s41594-025-01518-4
Share this article
Anyone you share the following link with will be able to read this content:
Get shareable link
Sorry, a shareable link is not currently available for this article.
Copy to clipboard
Provided by the Springer Nature SharedIt content-sharing initiative