The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones

Abstract

The sensitivity of the protein-folding environment to chaperone disruption can be highly tissue-specific. Yet, the organization of the chaperone system across physiological human tissues has received little attention. Here, we used human tissue RNAsequencing profiles to analyze the expression and organization of chaperones across 29 main tissues. We found that relative to protein-coding genes, chaperones were significantly more ubiquitously and highly expressed across all tissues. Nevertheless, differential expression analysis revealed that most chaperones were up-or downregulated in certain tissues, suggesting that they have tissue-specific roles. In agreement, chaperones that were upregulated in skeletal muscle were highly enriched in mouse myoblasts and in nematode's muscle tissue, and overlapped significantly with chaperones that are causal for muscle diseases. We also identified a distinct subset of chaperones that formed a uniformly-expressed, cross-family core group conducting basic cellular functions that was significantly more essential for cell survival. Altogether, this suggests a layered architecture of chaperones across tissues that is composed of shared core elements that are complemented by variable elements which give rise to tissue-specific functions and sensitivities, thereby contributing to the tissue-specificity of protein misfolding diseases. Significance StatementProtein misfolding diseases, such as neurodegenerative disorders and myopathies, are often manifested in a specific tissue or even a specific cell type. Enigmatically, however, they are typically caused by mutations in widely expressed proteins. Here we focused on chaperones, the main and basic components of the protein-folding machinery of cells. Computational analyses of large scale tissue transcriptomes unveils that the chaperone system is composed of core essential elements that are uniformly expressed across tissues, and of variable elements that are differentially expressed in a tissue-specific manner. This organization allows each tissue to fit the quality control system to its specific requirements and illuminates the mechanisms that underlie a tissue's susceptibility to protein-misfolding diseases.

Small heat-shock protein HSPB3 promotes myogenesis by regulating the lamin B receptor

“…Thus, HSPB3 may not exert housekeeping and redundant functions; HSPB3 may act as a muscle-specific chaperone regulating the folding/function of specialized nuclear substrates. Although HSPB3 is upregulated by MYOD in differentiating myoblasts 11 and is part of the muscle signature 19 , we do not know whether it takes part in the muscle differentiation program.…”

CoRe: A robustly benchmarked R package for identifying core-fitness genes in genome-wide pooled CRISPR-Cas9 screens

“…6A and Supplementary Table 3 ), thus worthy to be considered as bonafide true positive enrichments in human core fitness essential genes (the core-fitness families). These CFGs encompass most of the true positive controls used in our benchmark (ribosomal protein genes, proteasome, RNA polymerase [28]), as well as other plausible families, such as proteins involved in the initiation phase of eukaryotic translation [31], chaperonins [32], nucleoporins [33,34] and less immediate hits, such as AAA-ATPase [35,36] and WD repeat domain families [37,38].…”

“…6A and Additional File 8: Table S3), thus worthy to be considered as bonafide true positive enrichments in human core-fitness essential genes (the core-fitness families). These families encompass most of the true positive controls used in our benchmark (ribosomal protein genes, proteasome, RNA polymerase [40]), as well as other plausible families, such as proteins involved in the initiation phase of eukaryotic translation [42], chaperonins [43], nucleoporins [44,45] and less immediate hits, such as AAA-ATPase [46,47] and WD repeat domain families [48,49]. The coverage of these families was much larger for the more recent CFG sets when compared to the state-of-the-art CFGs, with ADaM and Sharma2020 performing best (average Recall across families = 57% and 54%, respectively).…”

Protein homeostasis imprinting across evolution

“…The conserved PN component across the vast majority of species is linked with protein production, folding and degradation, as well as responses to external or internal stimuli, activation or repression of anabolic and catabolic processes, to maintain cell homeostasis, as well as the proper localization of macromolecules. This comprises HSPs, which perform poorly in terms of separating the taxonomic kingdoms, but were recently shown to organize beyond the “de novo versus stress-inducible” scheme into a layered core-variable architecture in multi-cellular organisms (Shemesh et al, 2021). In addition to this, in order to cope with proteome complexity that arose with evolution, conserved core chaperones increased in abundance and new co-chaperone families appeared (Rebeaud et al, 2021).…”