UbiQ is proud to have contributed to research just reported in Molecular Cell. This collaborative research between New York University School of Medicine (project leader: Tony T. Huang), UbiQ and the University of Texas Health Science Center at San Antonio, describes how deubiquitinating enzymes (DUBs) regulate cleavage and stability of ubiquitin-fused ribosomal proteins (RPs) via catalytic and non-catalytic activities (Figure 1).

In eukaryotes, the small (40S) and large (60S) ribosomal subunits each contain a unique ribosomal protein that is encoded as a fusion protein with ubiquitin at its N-terminus. Each Ub-ribosomal protein fusion requires processing by deubiquitinating enzymes to generate ribosome assembly-competent ribosomal proteins, as well as contributing to the cellular ubiquitin pool. However, how Ub-RP fusions are processed by DUBs in human cells remains unclear. By examining the mechanism of Ub-fused RP processing in vitro and in human cells, we discovered that Ub-RP protein stability depends on interaction with DUBs that counteract lysine 29 and lysine 48 (K29/K48)-specific ubiquitination and proteasomal degradation. Using custom made Ub-RP derived activity-based probes, we identified a pool of DUBs that catalytically process Ub-fused RPs, but also DUBs that interact and prevent the degradation of Ub-RPs in a non-catalytic manner. Taken together, our results suggest that DUBs play a multifunctional role by both processing and stabilizing Ub-RPs to fine-tune protein homeostasis. 

Figure 1. Graphical abstract depicting how DUBs cleave ubiquitin-fused ribosomal proteins and physically counteract their targeting to the UFD pathway

Reference: Patchett et al. Deubiquitinases cleave ubiquitin-fused ribosomal proteins and physically counteract their targeting to the UFD pathway, Mol Cell 2025, DOI: 10.1016/j.molcel.2025.10.028