Regulation of Functional Proteome by the Heat Shock Response and Proteostasis Network

Abstract

Cellular health and proteome function is maintained by the proteostasis network (PN) comprised of molecular chaperones, transport pathways, the ubiquitin‐dependent proteasome, and autophagy clearance mechanisms. The dynamic properties of the PN are regulated by cell stress responses including the heat shock response (HSR) and the unfolded protein responses of the endoplasmic reticulum (UPRER) and mitochondria (UPRMITO). To understand the biology of organismal proteostasis, we have examined the properties of the PN in different tissues throughout the lifespan of C. elegans. The transition from development through reproduction into adulthood and aging places a tremendous demand on quality control processes and protein biogenesis. In early development, heat shock transcription factor HSF‐1 is essential, and target gene expression is co‐regulated with the cell cycle factor, E2F, to control a small subset of chaperone and PN genes involved in rapid anabolic growth. HSF‐1 is also involved in suppression of protein degradation pathways in early development. At reproductive maturity, the HSR is inhibited in somatic tissues by signals from the germ line stem cells that place repressive H3K27me3 chromatin marks at HS gene loci, repressing HSF‐1 DNA binding and transcription of chaperone genes, leading to the collapse of proteostasis in aging. These inhibitory signals on organismal proteostasis can be reversed genetically by overexpression of the jumonji demethylase, inhibition of germ line signaling, or induction of mitochondrial stress, either by mild downregulation of components of the electron transport chain, xenobiotics, and certain pathogenic bacteria to prevent the proteostasis collapse that occurs in early adult aging. These observations reveal that the regulation of molecular chaperones and other components of the PN by cell stress response pathways in aging is the basis for increased risk for misfolding and aggregation as occurs in neurodegenerative diseases and other protein conformational diseases.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.