α1-antitrypsin Deficiency: A Misfolded Secretory Protein Variant with Unique Effects on the Endoplasmic Reticulum

Abstract

In the classical form of α1-antitrypsin deficiency (ATD) a point mutation leads to accumulation of a misfolded secretory glycoprotein in the endoplasmic reticulum (ER) of liver cells and so ATD has come to be considered a prototypical ER storage disease. It is associated with two major types of clinical disorders, chronic obstructive pulmonary disease (COPD) by loss-of-function mechanisms and hepatic cirrhosis and carcinogenesis by gain-of-function mechanisms. The lung disease predominantly results from proteolytic damage to the pulmonary connective tissue matrix because of reduced levels of protease inhibitor activity of α1-anitrypsin (AT) in the circulating blood and body fluids. Cigarette smoking is a powerful disease-promoting modifier but other modifiers are known to exist because variation in the lung disease phenotype is still found in smoking and non-smoking homozygotes. The liver disease is highly likely to be caused by the proteotoxic effects of intracellular misfolded protein accumulation and a high degree of variation in the hepatic phenotype among affected homozygotes has been hypothetically attributed to genetic and environmental modifiers that alter proteostasis responses. Liver biopsies of homozygotes show intrahepatocytic inclusions with dilation and expansion of the ER and recent studies of iPS-derived hepatocyte-like cells from individuals with ATD indicate that the changes in the ER directly vary with the hepatic phenotype i.e there is much lesser alteration in the ER in cells derived from homozygotes that do not have clinically significant liver disease. From a signaling perspective, studies in mammalian cell line and animal models expressing the classical α1-antitrypsin Z variant (ATZ) have found that ER signaling is perturbed in a relatively unique way with powerful activation of autophagy and the NFκB pathway but relatively limited, if any, UPR signaling. It is still not known how much these unique structural and functional changes and the variation among affected homozygotes relate to the tendency of this variant to polymerize and aggregate and/or to the repertoire of proteostasis mechanisms that are activated.

Keywords: Autophagy; ER storage; Proteostasis.

Figure 1

Conceptual model for proteotoxicity in ATD. Liver cells from a putative protected host (left) can mitigate proteotoxicity by the action of ER degradation pathways (lower left) or putative protective cellular response pathways (lower right). In cells from a susceptible host (right) a subtle block (green bar) in either ER degradation pathways and/or the cellular response pathways leads to greater accumulation/proteotoxicity and chronic hepatic disease.

Figure 2

Induced pluripotent stem cells (iPS) model personalized variations in disease due to ATD. iPS cells from ATD patients with severe liver disease (severe LD), no liver disease (no LD) or wild type were tested by pulse-chase (center) and ultrastructural (right) studies. For the pulse-chase studies the disappearance of ATZ-specific radioactivity as measured by densitometric scanning of SDS-PAGE gels is shown as a function of chase (hrs). The results show that for severe liver disease there is slower disappearance of ATZ and massive inclusions (red arrows) compared to wild type with faster disappearance and normal ER morphology without inclusions (green arrow). For no liver disease the disappearance rate is intermediate and there is dilated ER (blue arrow) but no massive inclusions. The figure was created and kindly provided by Drs Edgar Tafaleng and Ira Fox.