Abstract
Maintenance of a functional proteome is achieved through the mechanism of proteostasis that involves precise coordination between molecular machineries assisting a protein from its conception to demise. Although each organelle within a cell has its own set of proteostasis machinery, inter-organellar communication and cell non-autonomous signaling bring forth the multidimensional nature of the proteostasis network. Exposure to extrinsic and intrinsic stressors can challenge the proteostasis network, leading to the accumulation of aberrant proteins or a decline in the proteostasis components, as seen during aging and in several diseases. Here, we summarize recent advances in understanding the role of proteostasis and its regulation in aging and disease, including monogenetic and infectious diseases. We highlight some of the emerging as well as unresolved questions in proteostasis that need to be addressed to overcome pathologies associated with damaged proteins and to promote healthy aging.
Highlights
Maintenance of a functional proteome is achieved through the mechanism of proteostasis that involves precise coordination between molecular machineries assisting a protein from its conception to demise
An effective interplay between components of the proteostasis network consisting of chaperones, co-chaperones, degradation machinery, translation control machinery, and adaptor proteins take cares of the balance in proteostasis
Proteostasis components, problems, and regulation Components of the proteostasis network Proteins are translated on ribosomes that act as scaffolds to assemble protein chaperones, which aid the nascent chains to reach their final functional structure
Summary
In the ER, proteostasis disequilibrium is sensed by IRE1 (the most conserved sensor among all eukaryotes), ATF6, and PERK (the last two branches are currently known to be present only in metazoans) These sense proteostasis problems in the ER to elicit an integrated stress response that increases ER chaperones, components of ER-associated degradation (ERAD) (clears misfolded proteins of ER) or autophagy, and ER volume (to decrease protein concentration)[36]. If proteostasis alteration modulates protein quality control and aggregation, it is likely to play an important role in the process of p53 amyloidogenesis The latter class of monogenetic dominant diseases, that result from a toxic gain of function, includes Huntington’s disease and different classes of spinocerebellar ataxia. As we unravel the role of proteostasis in different biological settings and close the gaps in knowledge, we hope that the excitement of discovery will be surpassed only by the usefulness of the discoveries in making our planet far more livable
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