Age-Dependent Regulation of Heat Shock Factor 1 in C. elegans

BSF Grant 2009187 Anat Ben-Zvi, Ben-Gurion University of the Negev, Beer-Sheva, Israel Richard I. Morimoto, Northwestern University, Evanston, IL, USA Age-Dependent Regulation of Heat Shock Factor 1 in Caenorhabditis elegans The long-term health of all cells is dependent on protein quality control. Protein folding and clearance networks sense and respond to the expression of misfolded and aggregation-prone proteins and activate cytoprotective cell stress responses to safeguard the proteome against damage, to maintain the health of the cell, and to enhance lifespan. Surprisingly, early in adulthood, C. elegans, cellular protein homeostasis (proteostasis) undergoes a sudden and widespread failure with marked consequences on proteostasis functions later in life.

Specifically, the cellular heat shock response that should, under proteotoxic conditions, adjust the expression of chaperones and other cytoprotective genes to ensure stress survival and recovery is severely dampened at the transition to adulthood. The focus of this grant was, therefore, to understand the underlying mechanism that leads to dysregulation of proteostasis during aging. Specifically, we aimed to understand how cell-nonautonomous signals regulate cellular proteostasis and how dynamic this regulation is during the lifespan of C. elegans.

Our work has identified the timing and tissue requirement for proteostasis collapse during adulthood and established that signals from the reproductive system cell-nonautonomously regulate somatic proteostasis. Using new tools and assays developed for this study, we determined that these cell- nonautonomous signals converge on the cellular heat shock response by remodeling chromatin accessibility at the onset of egg laying, thereby blocking transcription of stress inducible genes. Because proteostasis dysregulation is a common feature of aging and age-associated disease, this study has important implications for the development of new therapeutic interventions for late onset protein conformational diseases, such as Alzheimer’s and Parkinson’s disease.