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Review
. 2020 May 1;12(5):a034108.
doi: 10.1101/cshperspect.a034108.

Pharmacologic Approaches for Adapting Proteostasis in the Secretory Pathway to Ameliorate Protein Conformational Diseases

Jeffery W Kelly  1
Affiliations
Review

Pharmacologic Approaches for Adapting Proteostasis in the Secretory Pathway to Ameliorate Protein Conformational Diseases

Jeffery W Kelly. Cold Spring Harb Perspect Biol. .

Abstract

Maintenance of the proteome, ensuring the proper locations, proper conformations, appropriate concentrations, etc., is essential to preserve the health of an organism in the face of environmental insults, infectious diseases, and the challenges associated with aging. Maintaining the proteome is even more difficult in the background of inherited mutations that render a given protein and others handled by the same proteostasis machinery misfolding prone and/or aggregation prone. Maintenance of the proteome or maintaining proteostasis requires the orchestration of protein synthesis, folding, trafficking, and degradation by way of highly conserved, interacting, and competitive proteostasis pathways. Each subcellular compartment has a unique proteostasis network compromising common and specialized proteostasis maintenance pathways. Stress-responsive signaling pathways detect the misfolding and/or aggregation of proteins in specific subcellular compartments using stress sensors and respond by generating an active transcription factor. Subsequent transcriptional programs up-regulate proteostasis network capacity (i.e., ability to fold and degrade proteins in that compartment). Stress-responsive signaling pathways can also be linked by way of signaling cascades to nontranscriptional means to reestablish proteostasis (e.g., by translational attenuation). Proteostasis is also strongly influenced by the inherent kinetics and thermodynamics of the folding, misfolding, and aggregation of individual proteins, and these sequence-based attributes in combination with proteostasis network capacity together influence proteostasis. In this review, we will focus on the growing body of evidence that proteostasis deficits leading to human pathology can be reversed by pharmacologic adaptation of proteostasis network capacity through stress-responsive signaling pathway activation. The power of this approach will be exemplified by focusing on the ATF6 arm of the unfolded protein response stress responsive-signaling pathway that regulates proteostasis network capacity of the secretory pathway.

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Figures

Figure 1.
Figure 1.
Pharmacologic stress-responsive signaling pathway activation coordinates transcription and translation of chaperone pathways and folding enzymes that resculpt the folding free energy diagram of the mutant protein-of-interest in the endoplasmic reticulum (ER), enhancing its folding and minimizing misfolding, increasing the population of the mutant protein in the folded state. Pharmacologic chaperones bind to the folded state of the mutant protein, lowering its free energy, further increasing its population. Collectively, these mechanisms of action create more folded mutant protein that can engage the trafficking machinery, leading to increased function. (Figure from Mu et al. 2008b; reprinted, with permission, from Elsevier © 2008.)
Figure 2.
Figure 2.
Simplified depiction of the three arms of the unfolded stress response stress-responsive signaling pathway courtesy of Lars Plate. ER, Endoplasmic reticulum; ERAD, ER-associated degradation. (Figure from Wiseman et al. 2010; adapted, with permission, from Elsevier © 2010.)
Figure 3.
Figure 3.
Line drawing depiction of the chemical structure of the small-molecule ATF6 selective activator 147.
Figure 4.
Figure 4.
Line drawing depiction of the chemical structure of the small-molecule ATF6 selective activator 147-alkyne employed for target identification using affinity chromatography mass spectrometry-mass spectrometry. 147-alkyne undergoes oxidation to form a QM or a QI, which gets labeled covalently by protein conjugates. (Figure adapted from Paxman et al. 2018 and reprinted under the terms of the Creative Commons Attribution License.)
See this image and copyright information in PMC

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