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The HSP70-based molecular chaperone system in cytosol mediates various biological processes such as folding of newly synthesized proteins, refolding of misfolded proteins, translocation of proteins into organelles, assembly of proteins, and their degradation (; ; ; ). HSP70 chaperone proteins catalyze these biological processes with the aid of HSP40/DnaJ proteins and co-chaperones (Fig. 1A). HSP40/DnaJ proteins initially recognize substrate polypeptides, and transfer them to the substrate-binding domain of HSP70 proteins. During or just after transfer of the substrate polypeptide to HSP70, the J-domain of HSP40/DnaJ proteins accelerates hydrolysis of bound ATP in the nucleotide-binding domain of HSP70. The hydrolysis of ATP in the nucleotide-binding domain leads a conformational change of the substrate-binding domain to bind the substrate tightly. After binding of a substrate polypeptide to HSP70, various co-chaperones interact with the HSP70-polypeptide binary complex. Many co-chaperones in mammals contain a tetratricopeptide repeat (TPR) domain(s), and this domain recognizes the EEVD sequence at the carboxyl-terminal of cytosolic HSP70 proteins in eu-karyotes. The combination of these three components of the HSP70-based chaperone system is important to determine the proper destination of the substrate polypeptide.

Molecular chaperones are critical for cell survival by assuring proper protein folding in general, but chaperones, in particular the Hsp90 machinery, are also important for the activity of multiple specific client proteins involved in cellular signal transduction pathways. One class of extensively studied Hsp90 client is the steroid receptor subfamily of nuclear receptors. Chaperones are required for folding and stabilizing steroid receptors in a functionally competent state for hormone binding, and chaperones can also modulate steroid receptor responsiveness to hormone binding. In this chapter, we review recent advances in understanding the biochemical and physiological functions of a class of co-chaperones, the Hsp90-binding peptidylprolyl isomerases, that populate steroid receptor complexes.

Following exposure to environmental insults, the cells in most tissues dramatically increase the production of a group of proteins that are collectively known as “heat shock” or stress proteins (). This set of proteins functions as the major cellular defense against the accumulation of damaged proteins. One large group of heat shock proteins are molecular chaperones, including members of the Hsp70, Hsp90, Hsp104, Hsp40 (DnaJ), and small Hsp families (Hsp27, α-crystallins) (). Chaperones retard protein denaturation and aggregation by selectively binding unfolded domains in polypeptides (). Most of these chaperones are major cell constituents under normal conditions, where they are essential to ensure the proper folding and intracellular localization of newly synthesized polypeptides (). Their synthesis is further increased upon exposure to various proteotoxic stressors (including heat, heavy metals, hypoxia, and acidosis). The heat shock response is an evolutionary conserved mechanism that enables cells to better withstand these diverse physical and chemical insults ().

As nascent chains emerge from the ribosome, they interact with molecular chaperone proteins that prevent aggregation and promote protein folding. Chaperones such as Hsp70 and Hsp40 function together to protect nascent chains while still ribosome bound, and function with little if any specificity for the unfolded polypeptide. These interactions may be sufficient to promote folding, but in many cases they are not, and further binding between the nascent chain and more specific chaperones is needed. Two well-characterized chaperones that function downstream of Hsp70/Hsp40 are the chaperonins and Hsp90. Chaperonins are barrel-shaped multi-subunit proteins that have a chamber in which the unfolded polypeptide can attempt to fold. Hsp90 is known for its large number of co-chaperones or helper chaperones, and for folding of transcription factors and protein kinases among many other client types () ().

Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signaling proteins, as well as multiple mutated, chimeric, and/or overexpressed signaling proteins, that promote cancer cell growth and/or survival. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the inactivation, destabilization, and eventual degradation of Hsp90 client proteins, and they have shown promising anti-tumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, has completed phase I clinical trial, and more than 20 phase II trials of this agent are either planned or in progress. Phase I testing of a related Hsp90 inhibitor, 17-DMAG, is currently underway. Hsp90 inhibitors are unique in that, although they are directed toward a specific molecular target, they simultaneously inhibit multiple signaling pathways that frequently interact to promote cancer cell survival. Further, by inhibiting nodal points in multiple overlapping survival pathways utilized by cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. Hsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should be effective toward multiple forms of cancer. Further, because Hsp90 inhibitors also induce Hsf-1-dependent expression of Hsp70, and because certain mutated Hsp90 client proteins are neurotoxic, these drugs display ameliorative properties in several neurodegenerative disease models, suggesting a novel role for Hsp90 inhibitors in treating multiple pathologies involving neurodegeneration.

The focus of this commentary is gp96, the endoplasmic reticulum Hsp90 chaperone, its interactions with the innate and adaptive immune system, and how these interactions contribute to tumor immunity. The goal of this commentary, as embodied in the (paraphrased) quote from Aristotle, is to examine the “how do we know it.” And to avoid any errors of assumption, “it” is the hypothesis that gp96 associates with the antigenic peptide repertoire of the cell, a hypothesis that, if correct, identifies gp96 as a universal cross-presentation antigen.

Although the generally accepted concept is that exogenous stress proteins act as inflammatory mediators and “danger” signals to the immune system (), there is nowmuch evidence to indicate that stress proteins such as heat shock protein (Hsp)10 (; ), Hsp27 (; , Hsp60 (; ; ; de ; ; ; ; ; ; ; ; ; ; ), Hsp70 (; ; ; ), glucose-regulated protein (grp)78 (; , ; ; ; ), and gp96 (, ; ) can, under certain circumstances, exhibit anti-inflammatory activities.

The prevalence in the aging human population of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease is a burden on present society in terms of cost to health care systems and emotional stress on family members. What is the current status of research on these neurodegenerative disorders? Are these diseases entirely separate in character or are there commonalities? Are attempts to investigate the molecular basis of neurodegenerative diseases revealing clues that might lead to the development of rational therapeutics? Increasing evidence supports the view that the above-mentioned neurodegenerative diseases have common molecular mechanisms associated with protein misfolding and aggregation. These diseases have been termed “protein-misfolding disorders” or “protein-conformational disorders” that are characterized by the accumulation of intracellular and extracellular protein aggregates. This review explores the possibility that manipulation of the cellular stress response offers opportunities to counter conformational changes in proteins that trigger pathogenic cascades that result in neurodegenerative diseases.

The cohort of heat shock proteins (HSP) induced by cell stress becomes expressed at high levels in a wide range of tumors, and elevated levels of HSP are closely associated with a poor prognosis and treatment resistance. Increased HSP transcription in tumor cells is due both to loss of p53 function and elevated expression of proto-oncogenes such as HER2 and c-Myc and plays an essential role in tumorigenesis. The HSP family members overexpressed in cancer play overlapping, essential roles in tumor growth both by promoting autonomous cell proliferation and by inhibiting multiple death pathways. The HSP have thus become important and novel targets for rational anti-cancer drug design and HSP 90 inhibitors such as geldanomycin and 17-AAG are currently showing much promise in clinical trial while elevated HSP in tumors form the basis for chaperone-based immunotherapy.