The impact of genomic variation on protein phosphorylation states and regulatory networks

Abstract

Genomic variation impacts on cellular networks by affecting the abundance (e.g., protein levels) and the functional states (e.g., protein phosphorylation) of their components. Previous work has focused on the former, while in this context, the functional states of proteins have largely remained neglected. Here, we generated high‐quality transcriptome, proteome, and phosphoproteome data for a panel of 112 genomically well‐defined yeast strains. Genetic effects on transcripts were generally transmitted to the protein layer, but specific gene groups, such as ribosomal proteins, showed diverging effects on protein levels compared with RNA levels. Phosphorylation states proved crucial to unravel genetic effects on signaling networks. Correspondingly, genetic variants that cause phosphorylation changes were mostly different from those causing abundance changes in the respective proteins. Underscoring their relevance for cell physiology, phosphorylation traits were more strongly correlated with cell physiological traits such as chemical compound resistance or cell morphology, compared with transcript or protein abundance. This study demonstrates how molecular networks mediate the effects of genomic variants to cellular traits and highlights the particular importance of protein phosphorylation.

Large-scale changes of molecular network states explain complex traits

“…The top row shows correlation of the protein’s abundance with heat-induced lag. Fields in all other rows show allelic effects (difference in mean protein abundance between strains carrying the RM allele compared to the BY allele at the indicated loci) and asterisks indicate significant pQTL-target relations as described in (Grossbach et al ., 2022). Columns or proteins were ordered according to hierarchical clustering.…”

“…The largest differences were observed at markers coinciding or in linkage disequilibrium with hotspots of protein abundance regulation. Indeed, 7 of 12 pQTL hotspots (as detected in (Grossbach et al, 2022)) showed significant PT score differences at 5 % FDR and proteome-wide effects of pQTL hotspots were often correlated with the effects of chemical inhibition of PKA and TOR (Fig. S3A).…”

“…Using a collection of yeast segregants, we studied the genetic contribution to efficient outgrowth after temporary heat stress, which we refer to as 'heat resilience'. Transcriptomic, proteomic and phosphoproteomic measurements were employed to comprehensively chart the molecular network state in each segregant strain (Grossbach et al, 2022). We found genetic variants with effects on specific, heat-stress related proteins and others that determine resilience through a broad cellular program that is closely related to PKA and TOR signaling.…”

Arsenic perception and signaling: The yet unexplored world

“…The control of protein homeostasis and post-translational modifications (PTM) are also essential components for stress survival across different species (Zhang et al, 2015;Kosová et al, 2021). Strikingly, there is growing evidence that state changes of key regulatory proteins are associated with more dramatic functional alterations for the cell than protein abundance (Needham et al, 2019;Ochoa et al, 2019;Mehnert et al, 2020;Grossbach et al, 2022). Actually, several specific phosphorylation states have been correlated to a number of stress resistance traits in the context of a novel high-quality multi-omics QTL study in yeast, showing, for the first time at a global scale, the central importance of protein phosphorylation to adapt stress responses in living organisms (Grossbach et al, 2022).…”

“…Strikingly, there is growing evidence that state changes of key regulatory proteins are associated with more dramatic functional alterations for the cell than protein abundance (Needham et al, 2019;Ochoa et al, 2019;Mehnert et al, 2020;Grossbach et al, 2022). Actually, several specific phosphorylation states have been correlated to a number of stress resistance traits in the context of a novel high-quality multi-omics QTL study in yeast, showing, for the first time at a global scale, the central importance of protein phosphorylation to adapt stress responses in living organisms (Grossbach et al, 2022). However, the study of protein state changes in response to arsenic, including PTMs, is poorly developed, although there are some examples pointing to their relevance in arsenic signaling.…”