Human protein-clearance genes appear organized into core housekeeping and tissue-tuned layers that match tissue proteome needs.
Evidence
A resource-scale analysis of bulk and single-cell omics datasets, with experimental support for selected tissue-specific patterns, compared and genes across tissues and other proteostasis branches.
Caveat
The conclusions mainly come from expression, essentiality, interaction, and association patterns, so many tissue-specific functional and disease links remain inferential.
Simplified
Protein clearance is fundamental to proteome health. In eukaryotes, it is carried out by two highly conserved proteolytic systems, the (UPS) and the (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.: 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. Abbreviations
Key numbers
187
Essential Genes
Number of genes associated with Mendelian diseases.
294
Essential Genes
Number of genes associated with Mendelian diseases.
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