Variation in ubiquitin system genes creates substrate-specific effects on proteasomal protein degradation.

Abstract

Precise control of protein degradation is critical for life, yet how natural genetic variation affects this essential process is largely unknown. Here, we developed a statistically powerful mapping approach to characterize how genetic variation affects protein degradation by the ubiquitin-proteasome system (UPS). Using the yeast <i>Saccharomyces cerevisiae</i>, we systematically mapped genetic influences on the N-end rule, a UPS pathway in which protein N-terminal amino acids function as degradation-promoting signals. Across all 20 possible N-terminal amino acids, we identified 149 genomic loci that influence UPS activity, many of which had pathway- or substrate-specific effects. Fine-mapping of four loci identified multiple causal variants in each of four ubiquitin system genes whose products process (<i>NTA1</i>), recognize (<i>UBR1</i> and <i>DOA10</i>), and ubiquitinate (<i>UBC6</i>) cellular proteins. A <i>cis</i>-acting promoter variant that modulates UPS activity by altering <i>UBR1</i> expression alters the abundance of 36 proteins without affecting levels of the corresponding mRNA transcripts. Our results reveal a complex genetic basis of variation in UPS activity.