Genotype-by-environment interactions shape ubiquitin-proteasome system activity

In genotype-by-environment interactions (GxE), the effect of a genetic variant on a trait depends on the environment. GxE influences numerous organismal traits. However, we have limited understanding of how GxE shapes molecular processes. Here, we characterized how GxE shapes protein degradation, an essential molecular process that affects cellular and organismal physiology. Using 2 isolates of the yeast Saccharomyces cerevisiae, we profiled GxE in the ubiquitin-proteasome system (UPS), the primary protein degradation system in eukaryotes. By measuring UPS degradation activity toward 6 substrates that engage multiple distinct UPS pathways across 8 diverse environments, we discovered extensive GxE in the genetics of the UPS. The effects of all environments, including environments previously reported to affect UPS activity, differed between isolates and UPS substrates. To identify genomic regions underlying GxE for UPS activity, we mapped genetic influences on all our environment–UPS substrate combinations. Hundreds of locus effects varied depending on the environment. Most of these corresponded to loci that were present in one environment but not another (“presence/absence” GxE), while a smaller number of loci had opposing effects in different environments (“sign change” GxE). The number, genomic location, and type of GxE (presence/absence or sign change) of loci exhibiting GxE varied across UPS substrates. Loci exhibiting GxE were clustered at genomic regions that contain core UPS genes and at regions containing variation that affects the expression of thousands of genes, suggesting indirect contributions to UPS activity. Our results reveal complex interactions between the environment and the genetics of protein degradation.