Modeling DR and mRNA translation to understand adaptive mechanisms that promote health

项目总结

PROJECT SUMMARY Dietary restriction (DR) without malnutrition protects against age-related decline. Part of the response to DR involves restricting and redirecting translation to promote survival. On its own, genetically restricting translation increases lifespan and resistance to cellular stress, but little is known about the downstream mechanisms of regulation. The conserved nutrient sensing pathway governed by the target of rapamycin (TOR) positively regulates translation through the cap-binding complex (CBC) when nutrients are plentiful. We recently reported that restricting CBC activity increases survival during protein unfolding stress by upregulating the heat shock response (HSR), which maintains cellular health by regulating protein folding and turnover. Activation of the HSR involves upregulation of genes controlled by the transcription factor HSF1. One of these genes encodes the chaperone HSP90, which inhibits HSF1 at the protein level in a negative feedback loop. HSP90 translation and protein levels are downregulated during CBC restriction in C. elegans as well as during TOR inhibition in mouse tissue culture. We discovered that DR involving food dilution similarly suppresses synthesis of HSP90 relative to other cellular proteins. The HSR is universally recognized as critical to adaptation and survival, but the precise nature of its relationship to DR has been elusive. Translational regulation of HSP90 may act as a circuit in adaptation to DR involving the HSR. Our preliminary studies also show that increased survival to unfolded protein stress is driven by restricting the CBC in neurons or germ cells, which also limits reproduction. Interestingly, low CBC in these tissues upregulates the only Myogenic Response Factor (MRF) in C. elegans, HLH-1, which activates genes encoding structural components and chaperones in body muscle, the analog of skeletal muscle. Surprisingly, low CBC in muscle does not upregulate HLH-1 or provide robust protection from unfolded protein stress in that tissue but does increase reproduction. We propose that muscle is protected during DR to preserve function required for foraging and that low translation in muscle is a signal of inactivity associated with nutrient abundance. We will determine how low CBC activity associated with DR influences the HSR in different tissues and whether physical inactivity recapitulates the effects of low translation with respect to reproduction. We will also investigate the relationship between CBC activity and myogenic expression changes with respect to body muscle function, integrity, protection from protein unfolding stress, and lifespan. Finally, we will test the role of HSP90 in DR responses and in coordinating cross-talk between different tissues.