Conformational diseases are a class of disorders associated with aberrant protein accumulation in tissues and cellular compartments. Z α1-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-κB 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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Nuclear factor κB (NF-κB) is an inducible transcription factor that tightly regulates the expression of a large cohort of genes. As a key component of the cellular machinery NF-κB is involved in a wide range of biological processes including innate and adaptive immunity, inflammation, cellular stress responses, cell adhesion, apoptosis and proliferation. Appropriate regulation of NF-κB is critical for the proper function and survival of the cell. Aberrant NF-κB activity has now been implicated in the pathogenesis of several diseases ranging from inflammatory bowel disease to autoimmune conditions such as rheumatoid arthritis. Systems governing NF-κB activity are complex and there is an increased understanding of the importance of nuclear events in regulating NF-κB's activities as a transcription factor. A number of novel nuclear regulators of NF-κB such as IκB-ζ and PDZ and LIM domain 2 (PDLIM2) have now been identified, adding another layer to the mechanics of NF-κB regulation. Further insight into the functions of these molecules raises the prospect for better understanding and rational design of therapeutics for several important diseases.