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

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 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. Nevertheless, UPS and ALP subsystems had varied expression patterns. Furthermore, each system showed a layered organization. The larger layer included genes that were differentially expressed across tissues; tissue-specific upregulation was associated with tissue-specific functions, phenotypes, and disease susceptibility. The second smaller layer included genes that were stably expressed across tissues, more highly and widely expressed, had more protein interactions, and were more essential for growth, suggesting that they act as a core. 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 proteostasis network is organized hierarchically and is tailored to the proteome composition. This organization could contribute to and illuminate tissue-selective phenotypes.