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Histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA)-mediated correction of alpha 1-antitrypsin deficiency

Academic Article
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Overview

authors

  • Bouchecareilh, M.
  • Hutt, D. M.
  • Szajner, P.
  • Flotte, T. R.
  • Balch, William E.

publication date

  • November 2012

journal

  • Journal of Biological Chemistry  Journal

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.

subject areas

  • Calnexin
  • Cell Line
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum
  • Gene Expression
  • HCT116 Cells
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases
  • Humans
  • Hydroxamic Acids
  • Immunoblotting
  • Liver
  • Membrane Glycoproteins
  • Mutation
  • Oxidoreductases
  • Protein Folding
  • Protein Transport
  • Proteostasis Deficiencies
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • alpha 1-Antitrypsin
  • alpha 1-Antitrypsin Deficiency
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Identity

PubMed Central ID

  • PMC3488095

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M112.404707

PubMed ID

  • 22995909
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Additional Document Info

start page

  • 38265

end page

  • 78

volume

  • 287

issue

  • 45

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