Histone Deacetylase Inhibitor (HDACi) Suberoylanilide Hydroxamic Acid (SAHA)-mediated Correction of α1-Antitrypsin Deficiency

Abstract

Background: ␣1-Antitrypsin (␣1AT) deficiency (␣1ATD) is a consequence of defective folding, trafficking, and secretion of ␣1AT. Results: SAHA restores the secretion of an active form of Z-␣1AT in part through a calnexin-and HDAC7-sensitive dependent mechanism(s). Conclusion: SAHA may represent a potential therapeutic approach for ␣1ATD. Significance: SAHA is a regulator of the proteostasis biology of Z-␣1AT, favoring export of a functional form to serum.

Acetylation Stimulates the Epithelial Sodium Channel by Reducing Its Ubiquitination and Degradation

“…HDAC7 contributes to regulation of bone remodeling, T lymphocyte selection/activity, myocyte migration/ differentiation, and modulation of enzymes involved in intermediate metabolism (40 -43). HDAC7 is thought to contribute to the pathogenesis of diseases including cystic fibrosis (44) and ␣-1 antitrypsin deficiency (45). Most of these effects are mediated by its activity as a transcriptional corepressor.…”

Malfolded Protein Structure and Proteostasis in Lung Diseases

“…These response mechanisms are aimed at preserving proteostasis and include activation of the heat-shock response (16), antioxidant and redox signaling (ARS) (19), unfolded protein response (UPR) (20), mitochondrial response (mitoUPR) (18), and histone acetylation or deacetylation pathways (21,22). Recent work highlights the importance of the latter pathways in modifying the behavior of the protein fold through acetylation of surface lysine residues, which compete with degradation tagging pathways, including ubiquitination.…”

Alpha-1-Antitrypsin Deficiency Presenting as Neonatal Cholestasis: Predictors of Outcome and Effect of Ursodeoxycholic Acid

“…Three major ER stress response pathways include the ER overload response, which is characterized by nuclear factor kappa B activation, the unfolded protein response that involves upregulation of chaperones, foldases and degradation factors, and apoptosis. The use of a pharmacological chaperone therapy has already been tried in AAT deficiency patients but with not much success [23], and actually other drugs are under investigation [24,25].…”