Genotype-by-environment interactions shape ubiquitin-proteasome 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 across eukaryotic life. However, we have a limited understanding of how GxE shapes the molecular processes that give rise to organismal traits. Here, we characterized how GxE shapes protein degradation, an essential molecular process that influences numerous aspects of cellular and organismal physiology. Using two 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 towards six substrates that engage multiple distinct UPS pathways across eight 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 that contribute to GxE for UPS activity, we mapped genetic influences on all combinations of the eight environments and six UPS substrates. Hundreds of locus effects on UPS activity varied depending on the environment. Most of these cases 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 of loci exhibiting GxE, their genomic location, and the type of GxE (presence / absence or sign change) 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 highly complex interactions between the environment and the genetics of protein degradation.