Emergent properties of proteostasis in managing cystic fibrosis

Abstract

Cystic fibrosis (CF) is a consequence of defective recognition of the multimembrane spanning protein cystic fibrosis conductance transmembrane regulator (CFTR) by the protein homeostasis or proteostasis network (PN) (Hutt and Balch (2010). Like many variant proteins triggering 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 disrupted 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 therapeutic management of the emergent properties of the PN to control the energetics of CFTR folding biology may provide significant clinical benefit.

Figure 1.

The pathological Cystic Fibrosis triad. Illustrated are the three principle pathologic features observed in the clinic that define the CF disease triad in response to vCFTR. Each feature is likely to be subject to PN management either indirectly through the CFTR fold, or directly by PN components (Fig. 2).

Figure 2.

The Proteostasis Network. Shown are the interactions that comprise the PN, responsible for generating and maintaining the protein fold. Components comprising the PN outlined in the first layer (blue font) including the ribosome, Hsc70/Hsp70 and Hsp90 chaperones systems that direct folding, aggregases that promote aggregate formation, disaggregases that disassemble aggregates, as well as pathways that select proteins for degradation [e.g., the ubiquitin-proteasome system (UPS), endoplasmic reticulum (ER)-associated degradation (ERAD) systems, proteases, autophagic pathways, lysosomal/endosomal targeting pathways, and phagocytic pathways, the latter are responsible for the recognition, uptake, and degradation of extracellular proteins]. The second layer shows signaling pathways (green font) that influence the level and activity of components found in the first layer. The third layer (red font) includes genetic and epigenetic pathways, physiologic stressors, and intracellular metabolites that affect the activities defined by the second and first layer. Reproduced with permission from Elsevier Press (Fig. 2 in Powers et al. 2009).

Figure 3.

Cystic Fibrosis trafficking. (A) Illustrated is the trafficking itinerary of WT and three vCFTR (ΔF508, G551E, G1349D) through the exocytic pathway. Wild-type CFTR folds efficiently as indicated by achieving its native state in the folding landscape (lower left) and indicated by the green icon in the endoplasmic reticulum (ER). It is trafficked to the apical surface of lung airway epithelial cells (upper left, green) where it has normal channel function. During transport through the Golgi, WT-CFTR is processed from the band B ER associated glycoform to the band C complex glycoform (upper right). In contrast, the ΔF508 mutant is unstable in the ER (lower right) and as indicated by the red icon in the ER. It is efficiently degraded by ERAD. Typically, the only detectable form of ΔF508 is the band B glycoform restricted to the ER prior to degradation. The G551E and G1349D mutants (purple) are folded and traffic normally to cell surface. However, both have gating defect preventing channel function. The G551E and G1349D vCFTR only require a potentiator to open the channel and restore function. In contrast, ΔF508 requires the addition of a pharmacological chaperone (PC) corrector or alteration of the folding environment by a proteostasis regulator (PR) to restore delivery to the cell surface. (B) The vCFTR folding interactome. Genes involved are indicated in capitals. (Wang et al. 2006). Reproduced with permission from Elsevier Press (Fig. 2B in Wang et al. 2006). (See facing page for legend.)

Figure 3.

(Continued) (C) A key subset of PN factors that are now known to contribute to folding of vCFTR domains facing the cytosolic and the lumenal domain of the ER.

Figure 4.

PCs and PRs. Illustrated are two approaches to target the folding problem in CF. PC is a pharmacological chaperone that can be a corrector or a potentiator by binding directly to the misfolded protein and energetically stabilizing the fold; PR is a proteostasis regulator that alters the level or content of PN factors (colored balls) that would improve the vCFTR fold.

Figure 5.

Management of vCFTR functions by the PN. A hypothetical view of the activity of subsets of factors present in the PN that function at the indicated step of the vCFTR folding and trafficking itinerary. Adjustments to one or more nodes through the activity of PRs cannot only restore CFTR function, but re-establish connectivity to the biological network of the cell supporting normal physiology, thus alleviating the pathologic CF triad contributing to onset and progression of disease (Fig. 1).