Distinct stress conditions result in aggregation of proteins with similar properties

Abstract

Protein aggregation is the abnormal association of proteins into larger aggregate structures which tend to be insoluble. This occurs during normal physiological conditions and in response to age or stress-induced protein misfolding and denaturation. In this present study we have defined the range of proteins that aggregate in yeast cells during normal growth and after exposure to stress conditions including an oxidative stress (hydrogen peroxide), a heavy metal stress (arsenite) and an amino acid analogue (azetidine-2-carboxylic acid). Our data indicate that these three stress conditions, which work by distinct mechanisms, promote the aggregation of similar types of proteins probably by lowering the threshold of protein aggregation. The proteins that aggregate during physiological conditions and stress share several features; however, stress conditions shift the criteria for protein aggregation propensity. This suggests that the proteins in aggregates are intrinsically aggregation-prone, rather than being proteins which are affected in a stress-specific manner. We additionally identified significant overlaps between stress aggregating yeast proteins and proteins that aggregate during ageing in yeast and C. elegans. We suggest that similar mechanisms may apply in disease- and non-disease settings and that the factors and components that control protein aggregation may be evolutionary conserved.

Aggregation and Disaggregation Features of the Human Proteome

“…We also observed that proteins from the cytosolic ribosome had an insoluble fraction in unstressed conditions ( Fig EV2F). Similar observations have been made in yeast [13]. We speculate that this insoluble fraction represents ribosomal proteins in the nucleolus, where the ribosomes are assembled.…”

“…For example, chaperones and other proteostasis components were enriched in aggregates from aging nematode [9] and mice expressing huntingtin with disease-causing mutation [10]. Similarly, chaperones were found in aggregates when yeast cells were exposed to hydrogen peroxide, arsenite or azetidine-2-carboxylic acid [13]. Another similarity is the aggregation of ribosomal proteins in stress conditions, such as aging in nematode [8] and heat [12] or arsenite stress [15] in yeast.…”

“…Proteome-wide mass spectrometry-based studies have been previously used to characterize aggregation-prone proteins in different organisms and conditions. These include, for example, aging nematode [7][8][9], mice expressing disease-causing mutant of huntingtin protein [10], mice cells exposed to different stress conditions [11] and yeast under chemical or heat stress [12][13][14][15]. Although these studies involved quite different organisms and conditions, some similarities could be found.…”

Genome-wide, time-sensitive interrogation of the heat shock response under diverse stressors via ReporterSeq

“…We applied these stressors for between 20 minutes and 3 hours. As expected, the pleiotropic proteotoxic stressors and amino acid analogs known to cause accumulation of misfolded protein (Jacobson et al, 2012;Trotter et al, 2002;Weids et al, 2016) robustly activated the HSR. The other stressors, including amino acid starvation, glucose starvation, and the ER stressors DTT and tunicamycin, had milder effects on the HSR.…”

Large‐Scale Analysis of Redox‐Sensitive Conditionally Disordered Protein Regions Reveals Their Widespread Nature and Key Roles in High‐Level Eukaryotic Processes

“…Redox regulation is essential for the survival of all organisms, as cells constantly encounter the transient accumulation of reactive oxygen species (ROS). ROS may be generated exogenously or endogenously due to metabolic activity or inflammation, while subsequent oxidative damage can cause widespread protein unfolding and aggregation . It may also contribute to the pathogenesis of many different diseases, as well as to degenerative processes associated with aging .…”