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Review
. 2021 Nov 11;10(11):3121.
doi: 10.3390/cells10113121.

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

Selin Altinok  1 , Rebekah Sanchez-Hodge  1 , Mariah Stewart  1 , Kaitlan Smith  1 , Jonathan C Schisler  1
Affiliations
Review

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

Selin Altinok et al. Cells. .

Abstract

Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintain protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensure cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, with a concentration on cardioprotection, neuroprotection, cancer, and autoimmune diseases. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.

Keywords: cancer; cardioprotection; co-chaperones; heat shock proteins; neuroprotection; protein degradation; protein folding; protein quality control.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the writing of the manuscript or in the decision to publish.

Figures

Figure 1
Figure 1
Chaperone-mediated protein quality control. Chaperones, including HSP70 and HSP90, maintain cellular homeostasis through multiple pathways: assisting with de novo protein folding; multiprotein complex formation; protein shuttling throughout the cell; degradation of terminally misfolded proteins (via the ubiquitin-proteasome system (UPS) and chaperone-mediated autophagy (CMA); and refolding of misfolded proteins damaged by cellular stress. The chaperone system responds to multiple stressors, including the accumulation of misfolded proteins, heat shock, oxidative stress, and mechanical stress. Chaperone dysfunction contributes to numerous diseases discussed in this review.
Figure 2
Figure 2
Co-chaperones and neurodegenerative disease. The dysfunction of numerous co-chaperones contributes to neurodegenerative disease pathologies found throughout the brain. HSP70 and HSP90 co-chaperones including CHIP, HOP, FKBP51, FKBP52, and STG1 interact with proteins and aggerates associated with Alzheimer’s disease (Tau, Amyloid-Beta), Parkinson’s (Alpha-synuclein, Lewy Bodies), and Polyglutamine disease (Poly Q aggregates). The co-chaperones DNAJC3, DNAJC5, and CHIP protect against neuronal death in spinocerebellar ataxias.
Figure 3
Figure 3
The role of co-chaperones in cardiac protein quality control. Heat shock proteins, including HSP70, coordinate with co-chaperones to maintain proteostasis in the heart. Impairment of cardiac protein quality control can lead to distinct forms of heart disease, including left ventricular hypertrophy, dilated cardiomyopathy, and myocardial infarction. Loss-of-function in the co-chaperone proteins CryAB, BAG3, and CHIP alters chaperone function and the ability to maintain proteostasis, leading to heart disease. Missense mutations in CryAB and BAG3 cause heritable forms of cardiomyopathies (purple and orange). Loss of CryAB or BAG3 function can lead to left ventricular hypertrophy or increased susceptibility to infarction, respectively. Finally, the ability of CHIP to ubiquitinate regulatory proteins in cardiomyocytes (green) is necessary to prevent cardiac hypertrophy and cell death in response to myocardial infarction.
Figure 4
Figure 4
Co-chaperones and their implications across the cancer spectrum. Co-chaperones can associate with pro-folding and pro-degradation activities towards chaperone substrates. The co-chaperones listed indicate both the cellular triage condition, pro-folding (blue) or pro-degradation (orange), as well as the type of cancer (ENDO ADENO- endometrial adenocarcinoma, OSTEO- osteosarcoma). When appropriate, we included the specific BAG family member identifier; however, we did not indicate BAG2 associations with esophageal, oral, and thyroid cancer.
Figure 5
Figure 5
Co-chaperone network influences cancer cell proliferation. The decision to refold or degrade proteins represents an essential component of protein quality control. The co-chaperones HOP and CHIP compete for binding the EEVD motif located at the C-terminal tail of HSP70 and HSP90. The balance in HOP versus CHIP binding to HSPs results in a pro-folding or pro-degradation complex, respectively. In cancer, the pro-folding environment promotes cell proliferation by the constant re-folding of oncogenic proteins. In contrast, if CHIP–HSP binding is favored, oncogenic proteins can be degraded through the ubiquitin-proteasome system and ultimately inhibit cell proliferation. The cancers associated with these protein environments and identified substrates are provided. Additionally, the affinity of HOP and CHIP to HSPs are modified by post-translational modifications, including phosphorylation (P) and acetylation (Ac). Likewise, small molecules that target the C-terminus of HSP70 and HSP90 may influence co-chaperone occupancy. The C-terminal tail of HSP70/90 and post-translational modifications could be targeted to control the protein triage environment.
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