Adapting to stress - chaperome networks in cancer

Abstract

In this Opinion article, we aim to address how cells adapt to stress and the repercussions chronic stress has on cellular function. We consider acute and chronic stress-induced changes at the cellular level, with a focus on a regulator of cellular stress, the chaperome, which is a protein assembly that encompasses molecular chaperones, co-chaperones and other co-factors. We discuss how the chaperome takes on distinct functions under conditions of stress that are executed in ways that differ from the one-on-one cyclic, dynamic functions exhibited by distinct molecular chaperones. We argue that through the formation of multimeric stable chaperome complexes, a state of chaperome hyperconnectivity, or networking, is gained. The role of these chaperome networks is to act as multimolecular scaffolds, a particularly important function in cancer, where they increase the efficacy and functional diversity of several cellular processes. We predict that these concepts will change how we develop and implement drugs targeting the chaperome to treat cancer.

Fig. 1 |. Chaperome connectivity from normal cellular states to conditions characterized by increasing stress.

Under normal cellular conditions, the chaperome acts as a flexible and versatile connector of cellular pathways. Such flexibility is enabled by dynamic interactions among the chaperome members and between the major chaperome machineries. In these conditions, each chaperome machinery executes its set of dedicated functions with the use of individual sets of chaperones and co-chaperones. Such flexibility also permits a rapid chaperome rewiring when cells are exposed to acute stress (for example, heat) and certain chronic stresses to enable cellular stability and functionality. Networks are context-dependent, and the formation, re-wiring or restructuring of connectivities all depend on the applied molecular stress. Cellular stress increases the connectivity between distinct chaperome machineries, with the goal of increasing their functional diversity and competence. Certain stresses, such as MYC hyperactivation during oncogenesis (see the main text), can lead to a state of chaperome hyperconnectivity, where cellular demand requires maximal chaperome participation. Here, hyperconnectivity of the chaperome is executed by an increase in affinity between the chaperome machineries through their associated chaperones and co-chaperones. Thus, dynamic interactions between the chaperome members are characteristic of normal physiological conditions, but cellular stress alters the thermodynamics of such interactions, resulting in increased stability of chaperome complexes. Such a change also produces an altered functional interdependence among chaperome members. Most of the current data relates to the heat shock protein 90 (HSP90)-HSP70 chaperome, which we present as an example here, but the chaperome extends beyond these highly studied members. AHA1, activator of HSP90 ATPase 1; BAG1, BAG family molecular chaperone regulator 1; CD37L, HSP90 co-chaperone CDC37-ίike 1; CDC37, cell division cycle 37; FKBP5, FK-506-binding protein 5; HOP, HSP70-HSP90 organizing protein; NUDC, nuclear distribution protein C; PIHD1, PIH1 domain-containing protein 1; RPAP3, RNA polymerase Il-associated protein 3; sHSPs, small HSPs; TTC4, tetratricopeptide repeat domain 4.

Fig. 2 |. Functional gains from formation of multimeric chaperome scaffolding platforms under cellular stress.

a | Cellular stress results in the formation of multimeric chaperome complexes of increased stability These structures, which we call chaperome scaffolding platforms, form after stress to execute folding-independent functions and provide a template for the acquisition of new activities. Chaperome scaffolding platforms have the advantage of increased quaternary structure diversity, where formation of new connections between chaperome units may increase the function and versatility of such platforms^,. Stabilization of chaperome platforms by reducing the dynamic nature of chaperome-chaperome interactions may improve efficiency. These high-affinity chaperome complexes may help organize and maintain the function of the oncoprotein complement of a cancer cell in a tumour-specific and transformation-specific manner. In some cases, these context-dependent functions include the activation of signalling pathways in certain leukaemias, the processing of key mRNAs of lymphoma subtypes and the maintenance of the viral oncoproteome in gammaherpesvirus-associated malignancies. b | Formation of the chaperome platforms enables a dynamic adaptation to acute insults, providing a protective mechanism for cells under transient stress. When stresses become chronic, the adaptive functions meant to provide survival under acute stress become cemented and lead to maladaptive phenotypes associated with disease. AHA1, activator of HSP90 ATPase 1; CDC37, cell division cycle 37; HSP, heat shock protein; sHSPs, small HSPs.

Fig. 3 |. Chaperome networks use redundancy to protect from temporary or partial impairment.

An easy way to understand redundancy is to think of a technical network (for example, a power grid). In this model, when a primary path is unavailable, an alternate path can be instantly deployed to ensure minimal downtime and continuity of network services. In a biological system, redundancy has a similar connotation and provides chaperome networks with a rapid response to insults, whether genetic or environmental stress, or to drugs targeting any of the chaperome network components. Under normal conditions or perhaps low stress (that is, type 2 tumours), the networking capacity of the chaperome is in place but executed via flexible interactions between network components. Here, inhibition of chaperome units may be overcome by transfer of the workload to another chaperome or chaperome machinery In reality, networks cannot be infinitely redundant, and at some point, one may imagine that the entire network, including fail-safe systems, must be utilized; such is the case in conditions of high stress (such as with MYC hyperactivation), where the many connections between chaperome components become occupied and the network, which we call a hyperconnected chaperome network, reaches full capacity and may become ‘rigidʾ (REFS^,). Here, the range of adaptive responses is diminished, and cancer cells are now vulnerable to therapeutic interventions that target critical hubs and nodes. In this sense, the stresses encountered by a cancer cell leads to depletion of the networking capacity of the chaperome and stabilization of network connections. Unlike dynamic chaperome networks, which can restructure under stress, this hyperconnected network lacks ʿrestructuring capacityʾ and collapses after inhibition of a key chaperome network unit.