Chaperones as integrators of cellular networks: Changes of cellular integrity in stress and diseases

Abstract

The complex integrity of the cells and its sudden, but often predictable changes can be described and understood by the topology and dynamism of cellular networks. All these networks undergo both local and global rearrangements during stress and development of diseases. Here, we illustrate this by showing the stress-induced structural rearrangement of the yeast protein-protein interaction network (interactome). In an unstressed state, the yeast interactome is highly compact, and the centrally organized modules have a large overlap. During stress, several original modules became more separated, and a number of novel modules also appear. A few basic functions such as theproteasome preserve their central position; however, several functions with high energy demand, such the cell-cycle regulation loose their original centrality during stress. A number of key stress-dependent protein complexes, such as the disaggregation-specific chaperone, Hsp104 gain centrality in the stressed yeast interactome. Molecular chaperones, heat shock, or stress proteins became established as key elements in our molecular understanding of the cellular stress response. Chaperones form complex interaction networks (the chaperome) with each other and their partners. Here, we show that the human chaperome recovers the segregation of protein synthesis-coupled and stress-related chaperones observed in yeast recently. Examination of yeast and human interactomes shows that chaperones 1) are intermodular integrators of protein-protein interaction networks, which 2) often bridge hubs and 3) are favorite candidates for extensive phosphorylation. Moreover, chaperones 4) become more central in the organization of the isolated modules of the stressed yeast protein-protein interaction network, which highlights their importance in the decoupling and recoupling of network modules during and after stress. Chaperone-mediated evolvability of cellular networks may play a key role in cellular adaptation during stress and various polygenic and chronic diseases, such as cancer, diabetes or neurodegeneration.

The Heat Shock Connection of Metabolic Stress and Dietary Restriction

“…The life extending mechanism of these interventions is totally different from a partial food reduction, since (i) serial dilution of bacteria on the plates below a threshold (cca. 10 7 E. coli/ml) killed worms within two days [73], (ii) the longevity by bacterial deprivation was independent on FoxO/daf-16 and AMPK/aak-2 [80], (iii) the presence of metabolically active live bacteria, or their product prevented the food deprivation-induced longevity [79,82]. Indeed, both the longevity induced as well as a potent protection in several proteotoxic models by bacterial deprivation required hsf-1 [60].…”

“…The maintenance of proteome integrity is regulated by a network of genes that link stress responses and lifespan. A key player in this regard is the chaperone network [7][8][9][10] which is responsibe to maintain and modulate protein conformation, to protect proteins from misfolding and aggregation, to promote translocation and assembly and disassembly of macromolecular complexes [11][12][13][14]. The induction of heat shock response is mediated by the heat shock transcription factor 1 (HSF1) [15].…”

Creative elements: network-based predictions of active centres in proteins and cellular and social networks

“…Date-hubs are preferentially located in the overlaps of multiple modules, thus their connections are non-redundant and unique [35]. As an example, molecular chaperones have an inter-modular localization and are amongst those date-hubs that constitute the true central coordinators of the cellular network [41,42]. Several chaperones are also called stress proteins or heat shock proteins, and their centrality increases in protein-protein interaction networks after stress [41].…”

“…As an example, molecular chaperones have an inter-modular localization and are amongst those date-hubs that constitute the true central coordinators of the cellular network [41,42]. Several chaperones are also called stress proteins or heat shock proteins, and their centrality increases in protein-protein interaction networks after stress [41]. In other words: chaperones become key integrators when the cell experiences an unexpected situation, i.e.…”

“…However, creative elements are the 'life insurance' of complex systems helping their survival during any unexpected damage. Therefore, the number and importance of creative elements should increase if the complex organism experiences a fluctuating environment [35,41]. The adaptation of a large group of competing organisms to fluctuating environments can be described by the process of evolution.…”