The serine proteinase inhibitor alpha-1 antitrypsin (AAT) is produced principally by the liver from where it is secreted into the circulation and provides an antiprotease protective screen throughout the body. Mutations leading to deficiency in AAT are associated with liver and lung disease. The most notable is the Z mutation, which encodes a misfolded variant of the AAT protein in which the glutamic acid at position 342 is replaced by a lysine. ZAAT is not secreted effectively and accumulates intracellularly in the endoplasmic reticulum (ER) of hepatocytes and other AAT-producing cells. The ER has evolved a number of elegant mechanisms to manage the accumulation of incorrectly folded proteins; ZAAT interferes with this function and promotes ER stress responses and inflammation. Until recently it was thought that gain of function was the major cause of the liver disease whilst the lung disease was entirely due to loss of antiprotease protection in the lung. This belief is now being challenged with the discovery that ER stress is also activated in bronchial epithelial cells and inflammatory cells normally resident in the lung in ZAAT deficient individuals. Here we describe the gain of function effects of ZAAT. In particular we highlight the signalling pathways that are activated during ER stress in response to accumulation of ZAAT and how these events are linked to inflammation and may contribute to disease pathogenesis.
Keywords: Alpha-1 antitrypsin deficiency, apoptosis, endoplasmic reticulum stress, inflammation, NF-κB, unfolded protein
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