This two-level organization is conserved in multi-cellular eukaryotes. Whereas in prokaryotes the same chaperones carry both de novo protein folding and response to stress, unicellular eukaryotes evolved two separately regulated chaperone systems, a basal system and a stress inducible system, each composed of distinct members of the same chaperone families 28. Consequently, the chaperone system has been remodeled. The evolution of the sHSP family is more complex, as plants and some lower eukaryotes have more sHSPs than mammalian and higher eukaryotes 27. coli and 22 members in budding yeast to 49 members in human, whose distinct functionalities are not totally clear 13. The HSP40 family, for example, expanded from three members in E. The chaperone system has expanded considerably in evolution 25, 26. These observations imply that the quantitative composition of the chaperone system can improve or impair its proteostatic capacity. Likewise, chaperone downregulation or genetic aberration can cause diseases, such as mutation in the NEF co-chaperone BAG3 that leads to myopathy 24. For example, overexpression of the folding enzyme FKBP51 in a tau transgenic mouse model resulted in accumulation of tau and its toxic oligomers 21. Whereas chaperone overexpression typically improves the folding capacity of the chaperone system, overexpression of specific chaperones was shown to disrupt folding 19, 20, 21, 22, 23. However, the system also has limitations. The versatility and robustness of the chaperone system manifests in stress conditions, which lead to extensive upregulation of some chaperones. Likewise, co-chaperones containing the TPR domain, such as Hop, interact with both HSP70 and HSP90, thereby targeting substrates for either folding or degradation, respectively 18. For example, the same HSP70 chaperone can interact with different HSP40 co-chaperones, altering its substrate specificity 13. Most chaperones interact with multiple co-chaperones, and co-chaperones can interact with multiple chaperones, thereby modifying their function or the fate of their substrates. The chaperone system is highly versatile. Folding enzymes that catalyze folding-accelerating reactions, such as peptidyl prolyl cis– trans isomerization or protein disulfide isomerization 16, 17, are also considered as chaperones. Families of co-chaperones modulate the activity of main chaperones by regulating their ATPase cycle or the recognition, binding, or release of chaperone substrates, and include HSP10 9, HSP40 (DNAJ) 13, nuclear exchange factors (NEFs) 14, and co-HSP90 15. Families composing the main chaperone machinery, which modulate protein structure without participating in the final protein complex, include prefoldin 7, the small heat shock proteins (sHSP) 8, and the main ATP-hydrolyzing chaperones, HSP60 9, HSP70 10, HSP90 11, and HSP100 12.

In human cell lines, for example, they were shown to compose ~10% of the total proteome mass 6.Ĭhaperones have been grouped into families based on their molecular mass, common domains, protein structure similarity, and common function 1. In accordance with their fundamental roles, chaperones are abundant proteins. Across species, they promote de novo protein folding and protein maturation 1, protein translocation 2, protein-complexes assembly and disassembly 3, protein disaggregation and refolding 4, and protein degradation 5. Similar content being viewed by othersĬhaperones are highly conserved molecular machines that control cellular protein homeostasis (proteostasis). In this work, we expand the known functional organization of de novo versus stress-inducible eukaryotic chaperones into a layered core-variable architecture in multi-cellular organisms. Analysis of human organ development and aging brain transcriptomes reveals that these functional networks are established in development and decline with age. Together with variable chaperones, they form tissue-specific functional networks. Core chaperones are significantly more abundant across tissues and more important for cell survival than variable chaperones. We demonstrate via a proteomic analysis that the muscle-specific signature is functional and conserved. Through computational analyses of large-scale tissue transcriptomes, we unveil that the chaperone system is composed of core elements that are uniformly expressed across tissues, and variable elements that are differentially expressed to fit with tissue-specific requirements.

Yet, the organization of the chaperone system across physiological human tissues has received little attention. The sensitivity of the protein-folding environment to chaperone disruption can be highly tissue-specific.

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