Quality control processes are central for biological fidelity, and together with cell stress responses that detect and react to acute and chronic imbalances are essential for evolutionary robustness. In this review, we will discuss the current strategies used to tune the PN through targeting molecular chaperones and assess the potential of the chemical biology of proteostasis.Īll free-living prokaryotes and eukaryotes rely on the proteostasis network (PN), a conserved cellular machinery to support all aspects of protein biogenesis, to adapt to a complex and changing environment, and to determine organismal lifespan. Molecular chaperones have central roles in each of the arms of the PN (protein synthesis, folding, disaggregation, and degradation), leading to the proposal that modulation of chaperone function could have therapeutic benefits for the large and growing family of diseases of protein conformation including neurodegeneration, metabolic diseases, and cancer. Aging, exposure to physiological and environmental stress, and expression of mutant and metastable proteins can cause an imbalance in the protein folding landscape, resulting in the formation of non-native protein aggregates that challenge the capacity of the proteostasis network (PN), increasing the risk for diseases associated with misfolding, aggregation and aberrant regulation of cell stress responses. Protein homeostasis (proteostasis) is inextricably tied to cellular health and organismal lifespan.
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