Cell-Nonautonomous Regulation of Proteostasis in Aging and Disease

The functional health of the proteome is determined by properties of the proteostasis(definition) network (PN) that regulates protein synthesis, folding, macromolecular assembly, translocation, and degradation.In eukaryotes, the PN also integrates protein biogenesis across compartments within the cell and between tissues of metazoans for organismal health and longevity.Additionally, in metazoans, proteome stability and the functional health of proteins is optimized for development and yet declines throughout aging, accelerating the risk for misfolding, aggregation, and cellular dysfunction.Here, I describe the cell-nonautonomous regulation of organismal PN by tissue communication and cell stress-response pathways.These systems are robust from development through reproductive maturity and are genetically programmed to decline abruptly in early adulthood by repression of the heat shock response and other cell-protective stress responses, thus compromising the ability of cells and tissues to properly buffer against the cumulative stress of protein damage during aging.While the failure of multiple protein quality control processes during aging challenges cellular function and tissue health, genetic studies, and the identification of small-molecule proteostasis regulators suggests strategies that can be employed to reset the PN with potential benefit on cellular health and organismal longevity.P roteins exhibit an extraordinary diversity of sequence composition, conformational states, and properties, thus, keeping proteins optimally functional requires that the cell have robust quality control processes.Proteome health, therefore, requires a constant exchange between the intrinsic physical chemical properties of polypeptides and the cellular milieu in which they are expressed, folded, translocated, and degraded.These events are orchestrated by the proteostasis network (PN) that is comprised of ribosome quality control factors for protein syn-thesis, molecular chaperones essential for coand posttranslational folding, transport processes and the degradative machineries of the ubiquitin-proteasome and the autophagy(definition)-lysosome pathways (Balch et al. 2008;Powers et al. 2009; Labbadia and Morimoto 2015b;Balchin et al. 2016;Deuerling et al. 2019;Jayaraj et al. 2019).For proteins to be functional, the PN needs to be stable and robust to diverse conditions of environmental and physiological stress by modulating protein synthesis rates, the activities and levels of molecular chaperones to prevent