The proteostasis boundary in misfolding diseases of membrane traffic

Abstract

Protein function is regulated by the proteostasis network (PN) [Balch, W.E., Morimoto, R.I., Dillin, A. and Kelly, J.W. (2008) Adapting proteostasis for disease intervention. Science 319, 916-919], an integrated biological system that generates and protects the protein fold. The composition of the PN is regulated by signaling pathways including the unfolded protein response (UPR), the heat-shock response (HSR), the ubiquitin proteasome system (UPS) and epigenetic programs. Mismanagement of protein folding and function during membrane trafficking through the exocytic and endocytic pathways of eukaryotic cells by the PN is responsible for a wide range of diseases that include, among others, lysosomal storage diseases, myelination diseases, cystic fibrosis, systemic amyloidoses such as light chain myeloma, and neurodegenerative diseases including Alzheimer's. Toxicity from misfolding can be cell autonomous (affect the producing cell) or cell non-autonomous (affect a non-producing cell) or both, and have either a loss-of-function or gain-of-toxic function phenotype. Herein, we review the role of the PN and its regulatory transcriptional circuitry likely to be operational in managing the protein fold and function during membrane trafficking. We emphasize the enabling principle of a 'proteostasis boundary (PB)' [Powers, E.T., Morimoto, R.T., Dillin, A., Kelly, J.W., and Balch, W.E. (2009) Biochemical and chemical approaches to diseases of proteostasis deficiency. Annu. Rev. Biochem. 78, 959-991]. The PB is defined by the combined effects of the kinetics and thermodynamics of folding and the kinetics of misfolding, which are linked to the variable and adjustable PN capacity found different cell types. Differences in the PN account for the versatility of protein folding and function in health, and the cellular and tissue response to mutation and environmental challenges in disease. We discuss how manipulation of the folding energetics or the PB through metabolites and pharmacological intervention provides multiple routes for restoration of biological function in trafficking disease.

Figure 1. The FoldEx and FoldFx models defining the proteostasis boundary

(A) Illustrated are the interactive pathways that require the FRS to either complete the fold for export from the ER (FoldEx model) {Wiseman, 2007 #616} or for function (FoldFx model) {Powers, 2009 #613}, or contribute to misfolding, aggregation and degradation through the DRS. (B, C) Illustrated is the proteostasis boundary (PB) (indicated by the arrow) defined by kinetics of folding (z axis), kinetics of misfolding (y axis) and thermodynamics (x axis) reflecting a typical cellular composition of the PN (see {Wiseman, 2007 #190} for details). The location of a hypothetical cellular network facilitating cell function is indicated by the green nodes and edges, which, in a healthy cell (B) is protected by the PN and therefore beneath the PB. In disease (C), a mutation can result in misfolding (red node and edge) leading to a loss-of-function disease, or aggregation (black node and edge) that can lead to a gain-of-toxic function disease. See {Wiseman, 2007 #190}{Powers, 2009 #613} for a thorough treatment of the impact of mutation on the PN leading to human diseases. Panels B and C are reproduced with permission (Elsevier Press) in a modified form.

Figure 2. Compartmentalization and proteostasis boundaries

Illustrated is a hypothetical view of the differing organizations of the PB found in the indicated compartments. The differences in the shape of the PBs reflect the differences in the PN present in each of these compartments or in the extracellular space that promotes folding and/or maintenance of the fold.

Figure 3. Effect of the PB on stability of CFTR during folding and trafficking to the cell surface

Illustrated is the effect of two CFTR variants (ΔF508 and G551E) on trafficking through the exocytic pathway. Wild-type CFTR folds efficiently (indicated by the green) and is delivered to the cell surface where it has normal channel function (green). In contrast, the ΔF508 mutant is unstable in the ER (indicated by the red) and is efficiently degraded by the DRS. Addition of corrector or alteration of the folding environment by a proteostasis regulator may correct the folding problem in the ER and restore delivery to the cell surface where, given the proper environment, it may achieve a more normal level of channel function (light green). The G551E mutant normally folds efficiently in the ER (like WT) (green) and traffics to the cell surface, but has a defective channel (red) requiring either a potentiator (to activate the channel directly), or a proteostasis regulator that could affect the activity of the PN to improve open channel probability and hence, function.