Editorial: The HSP70 Molecular Chaperone Machines

The HSP70s belong to a small family of highly conserved ∼70 kDa enzymes that can use the energy of ATP-hydrolysis to modify the structure, and consequently the function, of specific native proteins, and to unfold, solubilize, and thereby reduce the cellular concentration of harmful misfolded proteins (Finka et al., 2016). Particular HSP70s are expressed constitutively in the cytosol of bacteria and in all the ATP-containing compartments of eukaryotic cells. In unstressed bacteria, plant, and animal cells, HSP70s are 0.5–2% of the total protein mass (Finka and Goloubinoff, 2013). They form the central hub of the chaperone network that controls all aspects of cellular protein homeostasis: protein de novo synthesis, protein translocation across membranes, native folding, and oligomer assembly. HSP70s also participate in the active removal of toxic protein aggregates by actively converting them into harmless degraded peptides, or into natively refolded functional proteins (Calamini and Morimoto, 2012; Finka et al., 2016). In immortalized human cancer cells and in naïve rat livers cells for example, HSPA8 is the major HSP70 species that is constitutively expressed in the cytosol, accounting for about half of the total mass of the HSP70s (Finka and Goloubinoff, 2013). In heat-shocked cells, particular HSP70s accumulate. Hence, following a 4 h mild fever-like heat-shock at 41C, the total mass of the HSP70s in Jurkat cells increases 1.6-folds, from ∼0.7% (at 37C) to ∼1.1% (Finka et al., 2015). Thus, although sharing 90% sequence identity with HSPA8, the cytosolic HSPA1A, which generally remains undetected in unstressed tissues, strongly accumulates during various abiotic stresses (Finka et al., 2015). Noticeably, non-heat-shocked cancer cells generally express constitutively abnormally elevated levels of HSPA1A that may even exceed the naturally high amounts of HSPA8. High expression levels of HSPA1A in otherwise unstressed tissues is thus a hallmark of malignancy and of poor survival outcome (Feder et al., 1992; Finka and Goloubinoff, 2013; Yang et al., 2015). The endoplasmic reticulum HSP70, HSPA5 (called BIP), and the mitochondrial HSP70, HSPA9 (calledmortalin) are the nextmost abundant HSP70 species. As in the case of cytosolic HSPA8, their concentration may also increase in response to heat-shock (Finka et al., 2015). In addition to their function in protein quality control, they act as pulling motors that import cytosolic polypeptides into their respective organelles. Assisted by over 30 different J-domain cochaperones in eukaryotes (Dekker et al.) and various nucleotide exchange factors (NEFs) (Bracher and Verghese), the HSP70s can control a great number of housekeeping cellular processes. They can use the energy of ATP-hydrolysis to convert active (alter)native protein complexes into differently active native polypeptides. Thus,