UbiDash: A UPS proteomic atlas for tissue-aware degrader design.

Targeted protein degradation repurposes endogenous E3 ubiquitin ligases to eliminate disease-driving proteins, yet the ligase toolkit deployed clinically remains narrow and largely tissue-agnostic. To support rational expansion of this toolkit, we built a harmonized pan-tissue proteomic atlas of the ubiquitin-proteasome system (UPS) by integrating four major resources: (1) CPTAC tumor and normal-adjacent tissues, (2) PRIDE healthy tissues, (3) the Pan-Cancer Proteome Atlas (TPCPA), and (4) the Cancer Cell Line Encyclopedia (CCLE). The resulting atlas spans 20 distinct tissue contexts and quantifies 5998 proteins, including 473 UPS components and 181 E3 ligases. Cross-resource validation confirmed successful harmonization while maintaining biological signal. We then derived a sample-level relative rank score (RRS) for every quantified UPS protein and identified 139 E3 ligases (of 181 detected) as being significantly tissue- or tumor-specific, including XIAP in lung cancer, KLHL7 in female-specific malignancies, and FBXL18 in head-and-neck and brain tumors. To enable broad accessibility, we developed UbiDash ( https://ruggleslab.shinyapps.io/UbiDash/ ), an interactive R Shiny platform that supports queries of UPS expression, mutation effects, protein co-regulation, and clinical associations. Together, the atlas and UbiDash provide a tissue-aware framework for ligase prioritization and rational degrader design that complements the mechanistic mutation- and lineage-driven UPS analyses described in our companion manuscript [1].