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  • Title: Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z alpha 1-antitrypsin deficiency.
    Author: Lawless MW, Greene CM, Mulgrew A, Taggart CC, O'Neill SJ, McElvaney NG.
    Journal: J Immunol; 2004 May 01; 172(9):5722-6. PubMed ID: 15100318.
    Abstract:
    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.
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