title: Histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA)-mediated correction of α1-antitrypsin deficiency.
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.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Marion
authors.initials: M
authors.lastname: Bouchecareilh
authors.forename: Darren M
authors.initials: DM
authors.lastname: Hutt
authors.forename: Patricia
authors.initials: P
authors.lastname: Szajner
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
authors.forename: William E
authors.initials: WE
authors.lastname: Balch
mesh_terms: D037281:Calnexin / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015151:Immunoblotting; D008099:Liver / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D021381:Protein Transport / Q000187:drug effects; D057165:Proteostasis Deficiencies / Q000097:blood / Q000235:genetics / Q000517:prevention & control; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077337:Vorinostat; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000097:blood / Q000235:genetics / Q000517:prevention & control*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008562:Membrane Glycoproteins; D000515:alpha 1-Antitrypsin; D037281:Calnexin; D000077337:Vorinostat; C405327:ERO1A protein, human; D010088:Oxidoreductases; C543273:HDAC7 protein, human; D006655:Histone Deacetylases