Proteostasis: a new therapeutic paradigm for pulmonary disease

Abstract

Among lung pathologies, α1AT, chronic obstructive pulmonary disease (COPD), emphysema, and asthma are diseases triggered by local environmental stress in the airway that we refer to herein collectively as airway stress diseases (ASDs). A deficiency of α-1-antitrypsin (α1AT) is an inherited genetic disorder that is a consequence of the misfolding of α1AT during protein synthesis in liver hepatocytes, reducing secretion to the plasma and delivery to the lung. Deficiency of α1AT in the lung triggers a similar pathological phenotype to other ASDs. Moreover, the loss of α1AT in the lung is a well-known environmental risk factor for COPD/emphysema. To date there are no effective therapeutic approaches to address ASDs, which reflects a general lack of understanding of their cellular basis. Herein, we propose that ASDs are disorders of proteostasis. That is, they are initiated and propagated by a common theme-a challenge to protein folding capacity maintained by the proteostasis network (PN) (see Balch et al., Science 2008;319:916-919). The PN is a network of chaperones and degradative components that generates and manages protein folding pathways responsible for normal human physiology. In ASD, we suggest that the PN system fails to respond to the increased burden of unfolded proteins due to genetic and environmental stresses, thus triggering pulmonary pathophysiology. We introduce the enabling concept of proteostasis regulators (PRs), small molecules that regulate signaling pathways that control the composition and activity of PN components, as a new and general approach for therapeutic management of ASDs.

Figure 1.

Managing proteostasis in human lung disease. Illustrated are the layers of interactions that facilitate the function of the proteostasis network to generate and maintain functional proteins in the lung and counter the challenges to the protein fold as occurs in α-1-antitrypsin (α1AT) and airway stress disease (ASD). The proteostasis network is composed of the components outlined in the first layer (in blue font), including the ribosome, chaperones, aggregases, and disaggregases that direct folding, 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 being responsible for the recognition, uptake, and degradation of extracellular proteins). The second layer includes signaling pathways (in green font) that regulate the levels and activity of components found in the first layer to allow adjustment of composition in response to folding stress such as found in α1AT deficiency and ASDs. The third layer (in red font) includes genetic and epigenetic pathways, physiologic stressors, and intracellular metabolites that affect the activities defined by the second and first layers. These are the genetic and epigenetic and environmental influences that challenge the protein fold and lead to α1AT deficiency and ASD. The proteostasis network is under dynamic biological control at all times and can be therapeutically adjusted by proteostasis regulators (PRs), a new class of small molecules that can be used to rebalance the proteostasis program to benefit human health (3, 5). Reproduced with permission from Reference (2).

Figure 2.

The proteostasis boundary that controls lung function in health and disease. The location of each node (or green sphere) in the network represents a corresponding protein's folding energetics (stability, x axis; folding kinetics, z axis; and misfolding kinetics, y axis). Each connection (green line) represents a physical or functional interaction that maintains the biological operation of the cell. The purple surface defines the proteostasis boundary (PB), defined by the composition of the proteostasis network (PN) in the lung. The location of the PB impacts the function of proteins based on their unique folding/misfolding kinetics and thermodynamic stability. It is shown as being the same for all proteins reflecting the general features of proteostasis capacity inherent in the highly abundant chaperone and degradative PN components (5). Many specialized components of the PN may augment the folding/misfolding kinetics or stability of a protein in the context of the general proteostasis program to achieve function. (a) All of the nodes driving normal lung function are within the proteostasis boundary of a healthy cell, indicating that their function is fully supported by the PN. (b) Mutations such as found in α1AT deficiency or in response to environmental challenges (e.g., allergens, air pollutants, or smoke leading to ASDs) can alter the folding kinetics or energetics of a protein, making their corresponding nodes fall outside the proteostasis boundary. This can lead to either loss of function (red node, i.e., Z-variant α1AT monomer) or aggregation (black node, i.e., Z-variant α1AT ER associated aggregate). Both states occur in α1AT deficiency. They likely strongly influence onset and progress of all ASDs. The double-ended green-red arrow at the base of the PB indicates that PN capacity can be increased by stress signaling pathways (green tip) or collapsed (red tip) by stress challenges that exceed the capacity of the PN to correct the folding problem (see text). Reproduced with permission from Reference (2).

Figure 3.

Role of proteostasis in cell-nonautonomous ASD. (a) Wild-type (WT) α1AT is correctly folded and secreted from hepatocytes in the presence of a healthy PN (large arrow), populating the lung with a protective anti-protease environment. (b) In α1AT deficiency and, in particular, Z-variant disease, α1AT is misfolded and poorly secreted (small arrow). The presence of variant α1AT in liver leads to progressive hepatocyte pathology by a cell-autonomous mechanism by challenging the capacity of the PN to deal with the folding problem. Proteostasis imbalance in the liver is influenced by the presence of both the misfolded monomer and the accumulation of aggregated Z-variant in the ER of the hepatocyte. Liver disease can be exacerbated by environmental insults including alcohol, toxins, and pathogens. (c) α1AT deficiency affects the lung by a cell-nonautonomous mechanism. The loss of anti-protease protection normally afforded by WT α1AT is similar to environmental insults such as pollution and cigarette smoke, which taxes pulmonary proteostasis capacity through oxidative stress and triggers inflammatory correction pathways. Pathogens can further exacerbate inflammatory responses to amplify loss of proteostasis capacity.