We now appreciate that newly synthesized polypeptide chain sequences must take-on folded, multi-dimensional structures to achieve function. The biological fold is very dynamic and therefore must be actively generated and maintained in the crowded environment of the cell to avoid misfolding and aggregation triggering pathology. Therefore, all biological folds require extensive folding assistance. A growing body of evidence reveals that protein function is generated and maintained by an evolutionary conserved folding program- the proteostasis network (PN) (Balch et al. (2008) Science, 319:916; Hutt and Balch (2010) 367:766). The PN is a modular, yet integrated biological system unique to each cell type that directs development and aging, and is responsive to a wide range of environmental, genetic and epigenetic signals that influence human physiology. The PN currently comprises not less than a collection of 2000 components that coordinately regulate biological protein synthesis, folding, function, and degradation (1–3). These form the Yin and Yang environment that promotes proteome balance (Hutt and Balch (2010) Science 367:766) required for healthy aging (3–6). Genetic changes in the amino acid compostion of the polypeptide chain often severely affect the dynamics of proteostasis to retain proteome balance. Given the multiplicity of factors that can trigger cell, tissue and organismal stress, it is not surprising that the PN has evolved to be highly versatile in its capacity to maintain proteome balance in human physiology. In this lecture, we review the new concept of proteostasis biology and the impact proteostasis has on our understanding of protein folding and function in healthy aging. It is now apparent that a very large number of diseases including, among others, neurodegenerative (Huntington, Parkinson, Alzheimers), type II diabetes, muscular dystrophies, cancer and channelopathies such as cystic fibrosis (CF), are sensitive to proteostasis program. As an example, we will focus on CF, as the misfolding of the cystic fibrosis transmembrane regulator (CFTR) in the most common form of disease (DF508/DF508) presents a major challenge to the proteostasis program. By linking the chemical and energetic properties of the protein fold with the composition of the PN we present a multi-dimensional view of proteostasis as an unanticipated feature of complex organismal function and healthspan in CF and other diseases. This new view suggests that the polypeptide chain sequence of CFTR and the proteostasis system operate as an integrated, multi-layered functional unit to generate and sustain protein folding dynamics in biology which is disrupted in human misfolding disease. We illustrate why therapeutic management of the PN will provide a rational basis for tackling some of the most challenging diseases facing mankind in the 21st century, including CF.
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