The human HSP70 family of chaperones: where do we stand?

Abstract

The 70-kDa heat shock protein (HSP70) family of molecular chaperones represents one of the most ubiquitous classes of chaperones and is highly conserved in all organisms. Members of the HSP70 family control all aspects of cellular proteostasis such as nascent protein chain folding, protein import into organelles, recovering of proteins from aggregation, and assembly of multi-protein complexes. These chaperones augment organismal survival and longevity in the face of proteotoxic stress by enhancing cell viability and facilitating protein damage repair. Extracellular HSP70s have a number of cytoprotective and immunomodulatory functions, the latter either in the context of facilitating the cross-presentation of immunogenic peptides via major histocompatibility complex (MHC) antigens or in the context of acting as "chaperokines" or stimulators of innate immune responses. Studies have linked the expression of HSP70s to several types of carcinoma, with Hsp70 expression being associated with therapeutic resistance, metastasis, and poor clinical outcome. In malignantly transformed cells, HSP70s protect cells from the proteotoxic stress associated with abnormally rapid proliferation, suppress cellular senescence, and confer resistance to stress-induced apoptosis including protection against cytostatic drugs and radiation therapy. All of the cellular activities of HSP70s depend on their adenosine-5'-triphosphate (ATP)-regulated ability to interact with exposed hydrophobic surfaces of proteins. ATP hydrolysis and adenosine diphosphate (ADP)/ATP exchange are key events for substrate binding and Hsp70 release during folding of nascent polypeptides. Several proteins that bind to distinct subdomains of Hsp70 and consequently modulate the activity of the chaperone have been identified as HSP70 co-chaperones. This review focuses on the regulation, function, and relevance of the molecular Hsp70 chaperone machinery to disease and its potential as a therapeutic target.

Heat Shock Protein 70 Negatively Regulates TGF-β-Stimulated VEGF Synthesis via p38 MAP Kinase in Osteoblasts

“…It is possible that HSP70 affects either Smad-dependent pathway or Smad-independent pathway of TGF-β signaling depending upon the cell species. On the other hand, it is well known that HSP70, conjuncted with the E3 ubiquitin ligase C-terminal Hsp70-interacting protein, promotes the ubiquitination and subsequent proteasomal degradation [10, 42]. It has been shown that the induction of HSP70 inhibits the TGF-β signaling through its direct binding to TGF-β type I receptor, resulting in the ubiquitination and degradation of the complex in embryonic kidney cells [43].…”

“…The HSP family have been recently classified into seven groups including HSPA (HSP70), HSPC (HSP90) and HSPH (HSP110) [6]. Among the members of HSPs, HSP70 (HSPA) ubiquitously exists in unstressed cells and functions as an ATP-dependent molecular chaperone for the assistance of folding newly synthesized proteins, and the translocation of proteins into the different cellular compartments [7-10]. Accumulating evidence indicates potent effects of HSP70 toward various diseases, such as cancer, infection and autoimmune diseases [4, 11].…”

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

“…Extracellular HSP70s carry out immunomodulatory functions as cross-presenters of immunogenic peptides via the major histocompatibility complex (MHC) found on the surfaces of cells (in all higher vertebrates), helping the immune system to recognize foreign substances. In humans a MHC complex is also called the human leukocyte antigen (HLA) and functions as a chaperokine which stimulates innate and adaptive immunity as well as stimulating the innate immune responses mediated by natural killer (NK) cells (see review of [24]). Note also that the "immunoglobulin heavy-binding protein" or Grp78 or BiP is located in the lumen of the ER.…”

DNAJB1/HSP40 Suppresses Melanoma Differentiation-Associated Gene 5-Mitochondrial Antiviral Signaling Protein Function in Conjunction with HSP70

“…The HSP70 family contains stress-inducible members (HSPA1) and constitutively expressed members (HSPA8) [23]. We found that polyI:C stimulation induced HSPA1 mRNA but not HSPA8 mRNA (Fig.…”

“…HSP40s (also referred to as J proteins) work as cofactors of HSP70s that are involved in various biological processes, such as protein refolding, protein interaction, and protein transport, by supporting protein conformational changes in an ATP-dependent manner [23]. DNAJB1 thus may interfere with MDA5 oligomerization by coupling with HSP70.…”