PROJECT SUMMARY / ABSTRACT
There is no change to the proposed work outlined in the parent R35 proposal (R35GM150481).
The integrity of the proteome is constantly being challenged. To maintain protein homeostasis, cells rely heavily
on highly integrated protein networks to provide surveillance and ensure proteins do not become susceptible to
aggregation, a driver of human neurological diseases and cancers. Paramount to these networks are molecular
chaperones and their regulators, which assist in protein folding, transport, and degradation. As the diversity of
proteins that require these chaperones increases, we have gained a broader understanding of the importance
of these regulators across many cellular processes. Recently, we discovered molecular chaperones also
influence cell metabolism by acting on key metabolic enzymes within glycolysis and purine biosynthesis to
efficiently produce the necessary biomolecules critical for their survival and proliferation. However, our
knowledge of how chaperones recognize and act on these enzymes remains largely elusive. The proposed
studies combine super-resolution fluorescence microscopy, biochemical and molecular biology tools, and
proteomic analyses to investigate the how chaperones regulate commonly observed phenomena across
metabolic pathways including the formation of phase separated metabolic enzyme assemblies to facilitate
substrate channeling, the folding of large multi-domain enzymes to drive tightly coupled activities, and the
induced degradation of metabolic enzymes by chaperone-mediated autophagy. These findings will deepen our
fundamental understanding of how cells respond to changes in nutrient availability to meet biomass demand,
provide insights into the molecular mechanisms of dysregulation that drive disease, and inspire new therapeutic
strategies targeting cell metabolism.