Histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA)-mediated correction of α1-antitrypsin deficiency.

Marion Bouchecareilh,Darren M Hutt,William E Balch,Terence R Flotte,Patricia Szajner

doi:10.1074/jbc.m112.404707

Abstract

α1-Antitrypsin (α1AT) deficiency (α1ATD) is a consequence of defective folding, trafficking, and secretion of α1AT in response to a defect in its interaction with the endoplasmic reticulum proteostasis machineries. The most common and severe form of α1ATD is caused by the Z-variant and is characterized by the accumulation of α1AT polymers in the endoplasmic reticulum of the liver leading to a severe reduction (>85%) of α1AT in the serum and its anti-protease activity in the lung. In this organ α1AT is critical for ensuring tissue integrity by inhibiting neutrophil elastase, a protease that degrades elastin. Given the limited therapeutic options in α1ATD, a more detailed understanding of the folding and trafficking biology governing α1AT biogenesis and its response to small molecule regulators is required. Herein we report the correction of Z-α1AT secretion in response to treatment with the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA), acting in part through HDAC7 silencing and involving a calnexin-sensitive mechanism. SAHA-mediated correction restores Z-α1AT secretion and serpin activity to a level 50% that observed for wild-type α1AT. These data suggest that HDAC activity can influence Z-α1AT protein traffic and that SAHA may represent a potential therapeutic approach for α1ATD and other protein misfolding diseases.

Highlights

Proper protein folding is essential to maintain cellular function and organismal health
It is delivered to the lung where ␣1AT is critical to prevent degradation of elastin, a key component ensuring the maintenance of lung elasticity. ␣1AT is considered as a metastable protein that is produced and secreted primarily by hepatocytes, with a poorly characterized contribution from lung macrophages and type II lung alveolar cells [14, 27, 33]. ␣1AT acts as an inhibitor of serine proteases such as human neutrophil elastase (HNE), cathepsin G, and proteinase-3 by capturing these proteins in an irreversible, higher molecular weight suicide complex through loop-sheet insertion and proteolytic cleavage [33,34,35]
We demonstrate that the suberoylanilide hydroxamic acid (SAHA)-dependent correction of Z-␣1AT secretion operates, at least in part, through HDAC7 by modulating a calnexinsensitive proteostasis pathway

Summary

Introduction

Proper protein folding is essential to maintain cellular function and organismal health. An examination of the Z-␣1AT protein levels in this same 4-h window revealed some important differences including 1) a statistically significant (ϳ50%) increase in the level of the ER-associated immature glycoform, 2) restoration of intracellular trafficking of Z-␣1AT as evidenced by the appearance of the steady-state level of mature Golgi processed glycoform, and 3) a 7-fold increase in the secretion of the Z-variant relative to the basal level seen upon DMSO treatment (Fig. 1C and supplemental Fig. S1G).

Results

Conclusion