| UCH37 (UCHL5) is a ubiquitin C‑terminal hydrolase–family deubiquitinase that associates with the 19S regulatory particle of the 26S proteasome and with the INO80 chromatin‑remodeling complex, where it edits ubiquitin chains on substrates to regulate proteasomal degradation and chromatin-associated processes. The enzyme contains an N‑terminal catalytic domain with the conserved Cys–His–Asp triad typical of UCHs and a C‑terminal tail that binds the proteasome receptor RPN13, and proteasome‑bound UCH37 shows markedly enhanced activity and altered substrate selectivity compared with the free enzyme. Proteasome‑associated UCH37 selectively cleaves at branch points of K48‑linked branched polyubiquitin, releasing short Ub oligomers from complex chain architectures, while leaving the remaining chains on the substrate, so UCH37 functions predominantly as a “debranching” DUB rather than a general chain‑trimming enzyme. Debranching by UCH37 promotes efficient engagement and translocation of branched‑ubiquitylated substrates into the proteasome: reconstituted proteasome assays show that removal of branch points accelerates degradation under multi‑turnover conditions, and pulse–chase proteomics in UCH37‑deficient cells reveals impaired global protein turnover, consistent with a role in facilitating clearance of heavily ubiquitylated clients. Distinct regulatory modes operate at the proteasome and in the INO80 complex, with RPN13 binding activating UCH37 toward branched chains at the proteasome and different partners modulating its activity at chromatin, indicating that interaction partners and local environment control when and where UCH37 edits ubiquitin signals. In cancer and neurodegenerative disease, UCH37 is one of several proteasome‑associated DUBs whose altered expression or activity perturbs ubiquitin‑proteasome system function; elevated UCH37 has been reported in multiple tumors, where changes in debranching capacity can influence stability of oncogenic or pro‑apoptotic substrates, while dysregulated ubiquitin signaling and proteasomal processing are common features in neurodegenerative settings where accumulation of ubiquitylated proteins occurs. |
