Pervasive convergent evolution and extreme phenotypes define chaperone requirements of protein homeostasis.

Maintaining protein homeostasis is an essential requirement for cell and organismal viability. An elaborate regulatory system within cells, the protein homeostasis network, safeguards that proteins are correctly folded and functional. At the heart of this regulatory system lies a class of specialized protein quality control enzymes called chaperones that are tasked with assisting proteins in their folding, avoiding aggregation and degradation. Failure and decline of protein homeostasis are directly associated with conditions of aging and aging-related neurodegeneration. However, it is not clear what tips the balance of protein homeostasis and leads to onset of aging and diseases. Here, using a comparative genomics approach we report general principles of maintaining protein homeostasis across the eukaryotic tree of life. Expanding a previous study of 16 eukaryotes to the quantitative analysis of 216 eukaryotic genomes, we find a strong correlation between the composition of eukaryotic chaperone networks and genome complexity that is distinct for different species kingdoms. Organisms with pronounced phenotypes clearly buck this trend. Northobranchius furzeri, the shortest-lived vertebrate and a widely used model for fragile protein homeostasis, is found to be chaperone limited while Heterocephalus glaber as the longest-lived rodent and thus an especially robust organism is characterized by above-average numbers of chaperones. Strikingly, the relative size of chaperone networks is found to generally correlate with longevity in Metazoa. Our results thus indicate that the balance in protein homeostasis may be a key variable in explaining organismal robustness.