Publication

Selenoprotein S/SEPS1 modifies endoplasmic reticulum stress in Z variant alpha1-antitrypsin deficiency.

Kelly, Emer
; 
Greene, Catherine M
; 
Carroll, Tomás P
; 
McElvaney, Noel G
; 
O'Neill, Shane J
Author
Kelly, Emer
 Greene, Catherine M
 Carroll, Tomás P
 McElvaney, Noel G
 O'Neill, Shane J
Advisors
Editors
Other Contributors
Departments
Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
Date
2009-06-19
Date Submitted
Keywords
Other Subjects
Subject Mesh
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
Planned Date
Start Date
Collaborators
Principal Investigators
Alternative Titles
Publisher
URI
https://hdl.handle.net/10147/127627
Abstract
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.
Language
en
Citation
Selenoprotein S/SEPS1 modifies endoplasmic reticulum stress in Z variant alpha1-antitrypsin deficiency. 2009, 284 (25):16891-7 J. Biol. Chem.
ISSN
1083-351X
eISSN
ISBN
DOI
10.1074/jbc.M109.006288
PMID
19398551
PMCID
Sponsorships
Funding Sources
Funding Amounts
Grant Identifiers
Methodology
Duration
Ethical Approval