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

J Biol Chem. 2012 Nov 2;287(45):38265-78. doi: 10.1074/jbc.M112.404707. Epub 2012 Sep 20.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Calnexin / genetics
  • Calnexin / metabolism
  • Cell Line
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum / metabolism
  • Gene Expression / drug effects
  • HCT116 Cells
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Immunoblotting
  • Liver / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mutation
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Protein Folding
  • Protein Transport / drug effects
  • Proteostasis Deficiencies / blood
  • Proteostasis Deficiencies / genetics
  • Proteostasis Deficiencies / prevention & control
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vorinostat
  • alpha 1-Antitrypsin / blood
  • alpha 1-Antitrypsin / genetics
  • alpha 1-Antitrypsin / metabolism*
  • alpha 1-Antitrypsin Deficiency / blood
  • alpha 1-Antitrypsin Deficiency / genetics
  • alpha 1-Antitrypsin Deficiency / prevention & control*

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Membrane Glycoproteins
  • alpha 1-Antitrypsin
  • Calnexin
  • Vorinostat
  • ERO1A protein, human
  • Oxidoreductases
  • HDAC7 protein, human
  • Histone Deacetylases