Deubiquitinases cleave ubiquitin-fused ribosomal proteins and physically counteract their targeting to the UFD pathway

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In eukaryotes, each ribosomal subunit includes a ribosomal protein (RP) that is encoded as a fusion protein with ubiquitin (Ub). In yeast, each Ub-RP fusion requires processing by deubiquitylating enzymes (DUBs) to generate ribosome assembly-competent RPs and contribute to the cellular Ub pool. However, how Ub-RP fusions are processed by DUBs in human cells remains unclear. Here, we discovered that Ub-RPs are substrates of the Ub-fusion degradation (UFD) pathway in human cells via lysine 29 and 48 (K29/K48)-specific ubiquitylation and proteasomal degradation. We identified a pool of DUBs that catalytically process Ub-RPs, as well as DUBs that physically occlude Ub-RP interaction with UFD pathway Ub E3 ligases to prevent their degradation in a non-catalytic manner. Our results suggest that DUBs both process and stabilize Ub-RPs, whereas the UFD pathway regulates levels of Ub-RPs that cannot be fully processed by DUBs to fine-tune protein homeostasis. • Cleavage-resistant ubiquitin-fused human ribosomal proteins (RPs) impair ribosome function • Unprocessed, Ub-fused RPs are targeted for proteasomal degradation by the UFD pathway • DUB activity-based probes for Ub-fused RPs identify Cezanne/OTUD7B and other DUBs • Catalytic activity-independent DUB association with Ub-RPs prevents their degradation Patchett et al. describe how the processing of ubiquitin-fused human ribosomal proteins can be regulated by both ubiquitin E3 ligases and DUBs to ensure proper ribosome function. Their findings show that the UFD pathway is critical for regulating the stability of ubiquitin-fused ribosomal proteins.

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