Ambre J. Sala1,2, Rogan A. Grant1,3, Ghania Imran1, Claire Morton1, Renee M. Brielmann1, Szymon Gorgoń2, Jennifer Watts4, Laura C. Bott1 and Richard I. Morimoto1 1Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, USA; 2Institute for Integrative Biology of the Cell (I2BC), Commissariat à l’Énergie Atomique et Aux Énergies Alternatives (CEA), Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Gif-sur-Yvette 91190, France; 3Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA; 4School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA Corresponding authors: ambre.salai2bc.paris-saclay.fr, r-morimotonorthwestern.edu Abstract

The ability to sense and respond to proteotoxic insults declines with age, leaving cells vulnerable to chronic and acute stressors. Reproductive cues modulate this decline in cellular proteostasis to influence organismal stress resilience in Caenorhabditis elegans. We previously uncovered a pathway that links the integrity of developing embryos to somatic health in reproductive adults. Here, we show that the nuclear receptor NHR-49, an ortholog of mammalian peroxisome proliferator-activated receptor α (PPARα), regulates stress resilience and proteostasis downstream from embryo integrity and other pathways that influence lipid homeostasis and upstream of HSF-1. Disruption of the vitelline layer of the embryo envelope, which activates a proteostasis-enhancing intertissue pathway in somatic cells, triggers changes in lipid catabolism gene expression that are accompanied by an increase in fat stores. NHR-49, together with its coactivator, MDT-15, contributes to this remodeling of lipid metabolism and is also important for the elevated stress resilience mediated by inhibition of the embryonic vitelline layer. Our findings indicate that NHR-49 also contributes to stress resilience in other pathways known to change lipid homeostasis, including reduced insulin-like signaling and fasting, and that increased NHR-49 activity is sufficient to improve proteostasis and stress resilience in an HSF-1-dependent manner. Together, our results establish NHR-49 as a key regulator that links lipid homeostasis and cellular resilience to proteotoxic stress.

Received April 17, 2024. Accepted May 16, 2024.