Base Sequence, Cell Line, DNA Primers, Endoplasmic Reticulum, Gene Expression, Genetic Variation, Glutathione Peroxidase, Heat-Shock Proteins, Humans, Membrane Proteins, NF-kappa B, Promoter Regions, Genetic, Recombinant Proteins, Selenium, Selenoproteins, Stress, Physiological, Transfection, alpha 1-Antitrypsin, alpha 1-Antitrypsin Deficiency
Alpha One Foundation.
Z alpha(1)-antitrypsin (ZAAT) deficiency is a disease associated with emphysematous lung disease and also with liver disease. The liver disease of AAT deficiency is associated with endoplasmic reticulum (ER) stress. SEPS1 is a selenoprotein that, through a chaperone activity, decreases ER stress. To determine the effect of SEPS1 on ER stress in ZAAT deficiency, we measured activity of the grp78 promoter and levels of active ATF6 as markers of the unfolded protein response in HepG2 cells transfected with the mutant form of AAT, a ZAAT transgene. We evaluated levels of NFkappaB activity as a marker of the ER overload response. To determine the effect of selenium supplementation on the function of SEPS1, we investigated glutathione peroxidase activity, grp78 promoter activity, and NFkappaB activity in the presence or absence of selenium. SEPS1 reduced levels of active ATF6. Overexpression of SEPS1 also inhibited grp78 promoter and NFkappaB activity, and this effect was enhanced in the presence of selenium supplementation. This finding demonstrates a role for SEPS1 in ZAAT deficiency and suggests a possible therapeutic potential for selenium supplementation.
Medicine and Health Sciences
Kelly E, Greene CM, Carroll TP, McElvaney NG, O'Neill SJ. Selenoprotein S/SEPS1 modifies endoplasmic reticulum stress in Z variant alpha1-antitrypsin deficiency. Journal of Biological Chemistry. 2009;284(25):16891-7.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.