Multiple functionalities of molecular chaperones revealed through systematic mapping of their interaction networks

Abstract

Chaperones are a highly interactive group of proteins that function globally in many cellular processes involved in maintaining protein homeostasis. Traditional biochemical assays typically do not provide a complete view of the intricate networks through which chaperones collaborate to promote proteostasis. Recent advances in high-throughput systematic analyses of chaperone interactions have uncovered that chaperones display a remarkable cooperativity in their interactions with numerous client proteins. This cooperativity has been found to be a fundamental aspect of a properly functioning cell. Aberrant formation or improper regulation of these interactions can easily lead to disease states. Herein, we provide an overview of the use of large-scale interaction assays, whether physical (protein-protein) or genetic (epistatic), to study chaperone interaction networks. Importantly, we discuss the ongoing need for such studies to determine the mechanisms by which protein homeostasis is controlled in the cell.

Chaperome heterogeneity and its implications for cancer study and treatment

“…Each tumor has an intrinsic need for a well-defined organization of protein networks. Providing a backbone for the structuring of these networks is the chaperome (48,49). Such function places the chaperome in a central position of cellular networks, which is the hub.…”

Molecular chaperones and protein quality control: an introduction to the JBC Reviews thematic series

“…To fully appreciate the importance of this cooperation, systems approaches and global interaction analyses are needed. Rizzolo and Houry (7) summarize the insight gained from different high-throughput approaches and explain why further efforts are required for a comprehensive understanding of the functional interplay of molecular chaperones.…”

Chaperome Networks – Redundancy and Implications for Cancer Treatment

“…The organization of these chaperones and co-chaperones is in the form of cooperating protein networks (Brehme et al 2019;Kumar et al 2018;Rizzolo and Houry 2019;Voisine et al 2010). Distinct and independent chaperome networks exist in eukaryotes, whereby a main chaperone, such as HSP90 or HSP70, functions with the aid of a number of cochaperones, each with a dedicated set of functions (Albanese et al 2006;Buchberger et al 1996;Diezmann 2014;Garcia and Morano 2014;Hartl et al 2011;Horwich 2014;Rospert and Chacinska 2006).…”

“…These studies also suggest that interactions of the chaperones with network components are of low affinity and transient, perhaps reflecting a dynamic character and an ability to quickly rewire the network during stress to achieve system stability. By their central role in such protein networks, chaperones may also connect with a large number of network modules, a placement that indicates their ability to participate in a variety of distinct, and vital, cellular processes (Echeverria et al 2011;Gong et al 2009;Korcsmaros et al 2007;Rizzolo and Houry 2019).…”