Proteasome activity maintains cell type-specific gene expression

Regulated proteolysis in eukaryotes relies on the ubiquitin-proteasome system, which is critical to myriad cellular functions, including protein quality control, cell cycle regulation, and DNA repair. Here, we provide evidence that proteasome activity is also essential for maintaining cell identity. This discovery was made by evaluating the impact of losing the ubiquitin-binding activity of proteasome substrate receptor hRpn10/PSMD4. The most dysregulated proteins in cells that express hRpn10 truncated before its ubiquitin interaction motifs (?UIM) are transcriptionally altered, with striking overrepresentation of proteins canonically restricted in expression to specific tissues. This dysregulation is partly driven by accumulation of the proteasome substrate anddeubiquitinase OTUD5, a known chromatin and transcriptional regulator. Our results thus identify previously unrecognized proteasome-dependent mechanisms to safeguard cell-type specific gene expression programs and expand proteasome biology to include governance of cell identity. Overall design: RNA-seq profiling of HCT116 cells (Either gene-edited to have a truncated version of rpn10 which is missing its ubiquitin interacting motif or WT), which were transfected with an OTUD5 siRNA or a scrambled control.