Co-chaperones fine-tune the function of heat shock protein 70 (Hsp70), whether to fold, hold, or degrade substrates in ensuring cellular protein homeostasis.

The molecular chaperone Hsp70 is a pivotal player in cellular protein quality control due to its wide range of substrates ranging from unfolded, native, to misfolded proteins. Increasing evidence suggests that Hsp70 decides the fate of proteins; however, the inherent rules that govern the decision-making capacity of Hsp70 are not clear. In this review, we have articulated the functions of Hsp70 with respect to proteostasis and established a link between its co-chaperones in deciding the fate of the substrate. The substrate binding of Hsp70 is mediated by its catalytic cycle where Hsp70 achieves high- and low-substrate-affinity ADP- and ATP-bound forms, respectively. This catalytic cycle of Hsp70 is maintained by co-chaperones J-domain proteins (JDPs), and nucleotide exchange factors (NEFs). JDPs bind to the ATP-bound form of Hsp70 and hydrolyze ATP that enhances substrate binding, whereas NEFs exchange ADP with ATP and facilitate substrate release. During evolution, several isoforms of Hsp70 and its co-chaperones have emerged which may have functional significance. Apart from facilitating the catalytic cycle of Hsp70, co-chaperones often mediate collaboration between Hsp70 and downstream protein quality-control pathways such as the ubiquitin proteasome system, autophagy, or disaggregase machinery. Therefore, co-chaperones have a significant role in Hsp70's triage decision of whether to fold, hold, or degrade.