Model systems of protein-misfolding diseases reveal chaperone modifiers of proteotoxicity

Abstract

Chaperones and co-chaperones enable protein folding and degradation, safeguarding the proteome against proteotoxic stress. Chaperones display dynamic responses to exogenous and endogenous stressors and thus constitute a key component of the proteostasis network (PN), an intricately regulated network of quality control and repair pathways that cooperate to maintain cellular proteostasis. It has been hypothesized that aging leads to chronic stress on the proteome and that this could underlie many age-associated diseases such as neurodegeneration. Understanding the dynamics of chaperone function during aging and disease-related proteotoxic stress could reveal specific chaperone systems that fail to respond to protein misfolding. Through the use of suppressor and enhancer screens, key chaperones crucial for proteostasis maintenance have been identified in model organisms that express misfolded disease-related proteins. This review provides a literature-based analysis of these genetic studies and highlights prominent chaperone modifiers of proteotoxicity, which include the HSP70-HSP40 machine and small HSPs. Taken together, these studies in model systems can inform strategies for therapeutic regulation of chaperone functionality, to manage aging-related proteotoxic stress and to delay the onset of neurodegenerative diseases.

Keywords: Chaperome; Chaperone; Co-chaperone; Disease models; Protein-misfolding disease; Proteostasis network.

Fig. 1.

Chaperones and co-chaperones identified in model-based studies of protein-misfolding diseases. Frequency is indicated based on 258 overall occurrences of 95 unique chaperones and co-chaperones, corresponding to 35 studies examined (see Table 1), of which 27 studies identified chaperones and co-chaperones. Chaperones or co-chaperones identified five or more times are highlighted in bold. Functional chaperome family membership is annotated by color (see key). HSP40, HSP60, HSP70, HSP90 and HSP100 are heat shock protein families of molecular chaperones as defined by the molecular weight (40, 60, 70, 90 or 100 kDa, respectively) of the original founding member; sHSP, small heat shock protein; TPR, tetratricopeptide repeat domain-containing co-chaperone; ER, endoplasmic reticulum-specific chaperones and co-chaperones; MITO, mitochondria-specific chaperones and co-chaperones.

Fig. 2.

Representation of chaperome functional families. Percentage representation of individual chaperome families as defined in the legend of Fig. 1 amongst 95 uniquely identified chaperones and co-chaperones, and amongst 258 overall occurrences of all chaperones and co-chaperones in all studies highlighted in Table 1.

Fig. 3.

HSP70 reaction cycle. (1) HSP40 binds to a client polypeptide and interacts with HSP70. (2) The ATP-bound form of HSP70 interacts with the unfolded polypeptide via its substrate-binding domain (SBD) and upon the hydrolysis of ATP to ADP stimulated by HSP40, a more stable interaction between the ADP-bound form of HSP70 and the polypeptide is formed. (3) A nucleotide exchange factor (NEF) interacts with the HSP70:polypeptide complex and (4) allows the exchange of ADP for ATP. (5) Following the exchange of ADP for ATP, both the polypeptide and NEF are released from HSP70. If the polypeptide is not properly folded, it can enter another round of the HSP70 reaction cycle.

Fig. 4.

Key chaperome modifier activities in misfolding-disease progression. HSP70s and their HSP40 co-chaperones function in a variety of basic cellular quality control processes. Distinct combinations of HSP70s and HSP40s facilitate folding (A), refolding of misfolded proteins (B), preventing aggregation (C) or promoting disaggregation (D), and degradation of misfolded proteins (E). Recent therapeutic strategies have focused on partitioning HSP70 activity towards prevention of aggregation (C), disaggregation (D) and degradation (E) to maintain the integrity of the proteome. sHSPs also manage misfolded proteins (B-E) and also act as cellular shields, interacting with misfolded or aggregated proteins to prevent aberrant interaction with cellular proteins (F). In this capacity, sHSPs can interact with disease protein aggregates, sequestering these toxic aggregates and protecting cells.