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The Journal of Immunology, 2004, 172: 5722-5726.
Copyright © 2004 by The American Association of Immunologists

Activation of Endoplasmic Reticulum-Specific Stress Responses Associated with the Conformational Disease Z {alpha}1-Antitrypsin Deficiency1

Matthew W. Lawless, Catherine M. Greene2, Alan Mulgrew, Clifford C. Taggart, Shane J. O’Neill and Noel G. McElvaney

Respiratory Research Division, Royal College of Surgeons in Ireland, Education and Research Center, Beaumont Hospital, Dublin, Ireland

Conformational diseases are a class of disorders associated with aberrant protein accumulation in tissues and cellular compartments. Z {alpha}1-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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