Human clearance systems have a layered architecture across tissues and cell types that supports varied proteome compositions

Protein clearance is fundamental to proteome health. In eukaryotes, it is carried out by two highly conserved proteolytic systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP). Despite their pivotal role, the basal organization of the human protein clearance systems across tissues and cell types remains uncharacterized. Here, we interrogated this organization using diverse bulk and single cell omics datasets. Relative to other protein-coding genes, UPS and ALP genes were more widely expressed, encoded more housekeeping proteins, and were more essential for growth, in accordance with their fundamental roles. Yet, UPS and ALP subsystems had varied expression patterns, and each system showed a layered organization. The smaller layer included genes that were stably and widely expressed across tissues, had elevated expression levels, interacted with more proteins, and were more essential for growth, suggesting that they act as a core. The second larger layer included genes that were differentially expressed across tissues. Tissue-specific upregulation of those genes was associated with tissue-specific functions, phenotypes, and disease susceptibility, as demonstrated computationally and experimentally. Last, we compared protein clearance to other branches of the proteostasis network. Protein clearance and folding were closely coordinated across tissues and more plastic than protein synthesis. Taken together, we propose that the human proteostasis network is organized hierarchically and is tailored to varied proteome compositions. This organization could contribute to and illuminate tissue-selective phenotypes. Abbreviations: ALP: autophagy-lysosome pathway; CDA: chaperone-directed autophagy; DUBs: deubiquitinases; ESCRT: endosomal sorting complexes required for transport; KS: Kolmogorov-Smirnov; MW: Mann-Whitney; TE: tissue-enriched; TS: tissue-specific; UBL: ubiquitin-like protein; UPS: ubiquitin-proteasome system.