BRCC36 is a Zn2+-dependent JAMM/MPN deubiquitinase (DUB) and is an essential component of the BRCC36 isopeptidase complex (BRISC), which blocks K63-linked ubiquitination and degradation of type I interferon receptor (IFNAR1) to enhance inflammatory signaling. The zinc-binding pocket of BRCC36 is conserved with other JAMM/MPN members, which makes selectively targeting BRCC36 difficult. To identify BRISC inhibitors, Chandler et al. conducted a biochemical screen examining changes in a K63-linked ubiquitin substrate using a library of kinase inhibitors. Characterization of potential hits revealed JMS-175-2 as a BRISC-selective inhibitor that blocked cleavage of ubiquitin chains but spared other DUB members. The JMS-175-2 compound series inhibited BRISC in a non-competitive manner, suggesting the compound was unlikely to target the zinc-binding pocket required for catalysis. Structural characterization by cryo-electron microscopy and mass photometry showed that JMS-175-2 acts as a molecular glue and promotes formation of a BRISC dimer complex composed of 16 subunits. Subsequently, these compounds were designated as BLUEs (BRISC molecular glues). Structural and hydrogen deuterium exchange–mass spectrometry analysis revealed that BLUEs contacted BRCC36 and two other BRISC subunits (Abraxas2 and BRCC45) to mediate a higher order dimer formation, which inhibited activity by blocking active site access and preventing ubiquitin binding. BLUE treatment in normal cells and cells derived from patients with an autoimmune disorder decreased IFNAR1 signaling and interferon-stimulated gene expression owing to increased IFNAR1 ubiquitination and reduced IFNAR1 cell surface levels. Although the efficacy of BLUEs to reduce inflammation in vivo requires further evaluation, the work from Chandler et al. reveals a unique strategy to selectively inhibit a DUB.
Original reference: Nat. Struct. Mol. Biol. https://doi.org/10.1038/s41594-025-01517-5 (2025)
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