Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z alpha 1-antitrypsin deficiency.
Conformational diseases are a class of disorders associated with aberrant protein accumulation in tissues and cellular compartments. Z alpha1-antitrypsin (A1AT) deficiency is a genetic disease associated with accumulation of misfolded A1AT in the endoplasmic reticulum (ER) of hepatocytes. We sought to identify intracellular events involved in the molecular pathogenesis of Z A1AT-induced liver disease using an in vitro model system of Z A1AT ER accumulation. We investigated ER stress signals induced by Z A1AT and demonstrated that both the ER overload response and the unfolded protein response were activated by mutant Z A1AT, but not wild-type M A1AT. Interestingly, activation of the unfolded protein response pathway required an additional insult, whereas NF-kappa B activation, a hallmark of the ER overload response, was constitutive. These findings have important implications for the design of future therapeutics for Z A1AT liver disease and may also impact on drug design for other conformational diseases.
Lawless
Matthew W
MW
Respiratory Research Division, Royal College of Surgeons in Ireland, Education and Research Center, Beaumont Hospital, Dublin, Ireland.
Greene
Catherine M
CM
Mulgrew
Alan
A
Taggart
Clifford C
CC
O'Neill
Shane J
SJ
McElvaney
Noel G
NG
D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000502:physiology; D002460:Cell Line; D006224:Cricetinae; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D018832:Molecular Chaperones / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D017510:Protein Folding; D021122:Protein Subunits / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection; D000515:alpha 1-Antitrypsin / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D019896:alpha 1-Antitrypsin Deficiency / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism
D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D018832:Molecular Chaperones; D016328:NF-kappa B; D021122:Protein Subunits; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin