Deciphering The Role Of DnaJ Chaperone Isoforms In Proteotoxic Stress Regulation

DnaJ chaperones, also known as J-proteins or HSP40s, are a family of chaperones that act as co-chaperones to HSP70. HSP70 chaperones are highly abundant, essential and promiscuous, that recognize misfolded proteins and act to refold them, prevent aggregation, or target them to degradation. DnaJs interact with HSP70 through the highly conserved J-domain, stimulating the ATP hydrolysis function of HSP70s. The DnaJ family has undergone a major expansion in evolution, with approximately 50 different family members in the human genome. Interestingly, recent work in our lab has found that the majority of human DnaJs additionally have different naturally occurring isoforms. Furthermore, many of these isoforms differ in the absence or presence of the J domain, which is essential for their interactions with HSP70, and plays a critical role in the chaperone activity. Additionally, we found that some DnaJs can form heterodimers. Here we systematically decipher the roles of different isoforms of 24 DnaJ proteins in the cellular response to different stress conditions. We try to understand the functional differences between DnaJ isoforms, their differential regulation within each of a series of proteotoxic stress conditions, as well as characterize their interactions with one another and to other proteins. Preliminary results show that different isoforms of some DNAJs have opposing functional effects on cell viability under osmotic stress (KCL), as well as differential interactions. Our ultimate goal is to unravel how DnaJ isoforms, and their heterodimerization, serve to expand the chaperone network complexity in its regulation in response to proteotoxic challenges.