HSP90 et al.: Chaperome and Proteostasis Deregulation in Human Disease
HSP90 action as a conserved chaperone is fundamental to the folding and maturation of a large fraction of structurally and functionally diverse proteins. Through its wide spectrum of clients and their connectivity within the proteome, HSP90 is a key factor in the processes that maintain cellular proteostasis, referred to as the proteostasis network (PN). Besides HSP90, hundreds of additional molecular chaperones and co-chaperones act together in complexes and intricate networks to maintain the cellular native folding environment, avoid misfolding, and redirect non-native folding intermediates back to their native state or towards clearance. The ensemble of all cellular chaperones and co-chaperones constitute the chaperome, which acts to regulate and maintain proteome functionality. Recent insights derived from systematic studies have revealed vast imbalances to cellular proteostasis reflected by chaperome deregulation from aging, to neurodegenerative diseases, and cancers. Deregulation states along with specific chaperome connectivity can represent biomarkers for certain diseases. HSP90 is not acting in isolation but as a component of a comprehensive and dynamic chaperome interactome network. Therefore, a detailed understanding of systems-level alterations of chaperome biology is fundamental towards a better understanding of HSP90 action and its therapeutic targeting in health and disease.
KeywordsChaperome Chaperone Co-chaperone Heat shock protein HSP90 Proteostasis Proteostasis network (PN)
Heat shock protein
Heat shock protein 90
The authors would like to acknowledge Richard Morimoto, Marc Vidal, Andreas Schuppert, Julio Saez-Rodriguez, Angelina Sverchkova, and Ali Hadizadeh-Esfahani for their support and contributions to the authors’ research referenced in this chapter. Figure 27.1 reproduced from Brehme and Voisine, Disease Models & Mechanisms (2016) 9, 823–838, https://doi.org/10.1242/dmm.024703 with permission of Disease Models & Mechanisms.