Emergent Properties of Proteostasis in Managing Cystic Fibrosis

Cystic fibrosis (CF) is a consequence of defective recognition of themultimembrane spanning protein cystic fibrosis conductance transmembrane regulator (CFTR) by the protein homeo-stasis or proteostasis network (PN) (Hutt and Balch (2010). Like many variant proteins trig-gering misfolding diseases, mutant CFTR has a complex folding and membrane trafficking itinerary that is managed by the PN to maintain proteome balance and this balance is dis-rupted in human disease. The biological pathways dictating the folding and function of CFTR in health and disease are being studied by numerous investigators, providing a unique opportunity to begin to understand and therapeutically address the role of the PN in disease onset, and its progression during aging.We discuss the general concept that thera-peutic management of the emergent properties of the PN to control the energetics of CFTR folding biology may provide significant clinical benefit. CYSTIC FIBROSIS AS A SYSTEMS DISEASE Cystic fibrosis (CF) is an inherited disordercaused by mutations affecting the func-tion of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP gate