The Serine Proteinase Inhibitor Z Alpha-1 Antitrypsin: Acting on the NF-kappaB System for Cytotoxicity pp.107-124
Authors: (Matthew William Lawless, Department of Clinical Medicine, Trinity College, Dublin, St. James Hospital, Ireland)
Abstract: The serine proteinase inhibitors Alpha-1 Antitrypsin (A1AT) and its mutant protein the so-called 'Z' mutation in A1AT deficiency encodes a glutamic acid-to-lysine substitution at position 342 in A1AT and is the most common A1AT allele associated with disease. In recent years, several important research advances in the cell biology of this aggregation-prone serine proteinase inhibitors and its pathobiological mechanisms for disease onset have proven paramount to our understanding of Z A1AT deficiency. The liver disease associated with Z A1AT, occurs in up to 15% of A1AT-deficient individuals, a result of toxic gain-of-function mutations in the A1AT gene, which cause the A1AT protein to fold aberrantly and accumulate in the endoplasmic reticulum of hepatocytes. The lung disease is associated with loss-of-function, specifically decreased anti-protease protection on the airway epithelial surface. Most strikingly, this polymer has now been revealed to activate the NF-kappaB (NFκB) system and cause cytotoxicity by a pathway that is independent of the unfolded protein response (UPR). NFB which is an inducible transcription factor which regulates the expression of a range of genes involved in important biological processes such as the innate and adaptive immunity, inflammation, cellular stress responses, cell adhesion, apoptosis and proliferation. This chapter addresses the structural basis of this serine proteinase inhibitor (Z A1AT) and how the ordered accumulation of this polymer activates the NFB system affecting cell death. Furthermore, we place these findings in the context of the histone code in order shed light on how to target the NFB system in a specific fashion for the setting of Z A1AT disease.