[
International Worm Meeting,
2021]
The proteostasis network (PN) comprises the cellular machineries that regulate protein synthesis, folding, and degradation, to promote proteome integrity. Reduced functionality of the PN during aging results in the accumulation of misfolded and aggregated species that are detrimental for cellular health, and is a hallmark of many age-associated diseases. In multicellular organisms, the PN is regulated by transcellular communication to coordinate proteostasis across tissues and organs in response to physiological and environmental stimuli. The reproductive system in particular is a critical tissue for proteostasis regulation, and signals from the germline initiate the decline of somatic proteostasis and cellular stress responses at reproductive maturity in C. elegans. Here we show that stress resilience and proteostasis are also regulated by embryo-to-mother communication in reproductive adults. To identify genes that act directly in the reproductive system to influence somatic proteostasis, we performed a tissue-targeted RNAi screen for germline modifiers of muscle polyglutamine aggregation. We found that inhibiting the formation of the extracellular vitelline layer of the fertilized embryo inside the uterus suppresses aggregation in multiple somatic tissues and improves maternal stress resilience in an HSF-1-dependent manner. Damage to the vitelline layer of the embryo also prevents the collapse of the heat shock response that normally occurs in early adulthood. This embryo-to-mother pathway relies on DAF-16/FOXO activation in vulva tissues to maintain organismal stress resilience, suggesting that the vulva senses the integrity of the fertilized embryo to detect damage and initiate the organismal response. Gene expression analysis of vitelline layer defective animals using RNA sequencing also revealed that genes involved in lipid metabolism are activated, which is accompanied by elevated fat stores, suggesting a link between fat metabolism and proteostasis in these animals. Our findings reveal a previously undescribed transcellular pathway that links the integrity of the developing progeny to somatic proteostasis regulation and lipid metabolism in the parent. This pathway may serve to reassess commitment to reproduction and promote somatic endurance when progeny production is compromised.
[
International Worm Meeting,
2021]
Stress and aging can compromise cellular proteostasis and lead to the loss of proteome integrity, a hallmark of many degenerative diseases. Efforts to maintain the functional capacity of the proteostasis network hold promise for prolonging organismal health and reducing the burden of disease, however, the underlying basis for the decline are at present unknown. This is in part due to a lack of available methods for observing the consequence of stressful stimuli on proteome integrity in real time. Here we report a new genetically-encoded biosensor that allows quantitative assessment of proteostasis network capacity in living Caenorhabditis elegans. It is based on a metastable version of dihydrofolate reductase and a conditional proteasome-targeting signal, thereby linking conformational state to protein levels, and fused to a fluorescent protein tag for visualization inside cells. The sensor reveals systemic remodeling of the proteostasis network and identifies distinct cellular states in stress, early aging, and C. elegans models of human disease. Our results indicate that this multi-modal biosensor is a convenient tool for in vivo investigations into proteostasis network regulation in health and disease states.