Modulating Hsp90 function to regulate organismal proteostasis and aging.
Hsp90 is an ancient molecular chaperone that plays central roles in the regulation of protein homeostasis (proteostasis). Hsp90 is also a key regulator of HSF1 and the cytosolic heat shock response. For example, knockdown or inhibition of Hsp90 function induces HSF1 activity, resulting in increased chaperone expression. Certain Hsp90 inhibitors have even been identified as geroprotectors that extend the lifespan of C. elegans. While increased HSF1 activity protects against age-associated accumulation of aggregated proteins, it can also contribute to malignancy under certain conditions.
Using the metazoan C. elegans we have shown that altering the expression levels of Hsp90 in in either the gut or the nervous system induces protective chaperone expression cell nonautonomously across tissues and independent of HSF1. This shows that Hsp90 acts as an integrator of organismal stress responses. We coined this process “transcellular chaperone signaling” (TCS). Activation of TCS results in longevity, increased health span and stress resilience.
Our lab investigates the molecular mechanism how Hsp90 induces protective cross-tissue stress signaling. Specifically, we aim to determine 1) how Hsp90 function is modified in response to a variety of stress conditions in a tissue-specific manner, and reciprocally, 2) how we can modulate Hsp90 tissue-specific activity to promote long-term health and protein quality control throughout aging.