Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency.
AuthorsCarroll, Tomás P
Greene, Catherine M
O'Connor, Catherine A
Nolan, Aine M
O'Neill, Shane J
McElvaney, Noel G
AffiliationRespiratory Research Division, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland. email@example.com
MeSHAmino Acid Substitution
Gene Expression Regulation
alpha 1-Antitrypsin Deficiency
MetadataShow full item record
CitationEvidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency. 2010, 184 (8):4538-46 J. Immunol.
JournalJournal of immunology (Baltimore, Md. : 1950)
AbstractThe hereditary disorder alpha-1 antitrypsin (AAT) deficiency results from mutations in the SERPINA1 gene and presents with emphysema in young adults and liver disease in childhood. The most common form of AAT deficiency occurs because of the Z mutation, causing the protein to fold aberrantly and accumulate in the endoplasmic reticulum (ER). This leads to ER stress and contributes significantly to the liver disease associated with the condition. In addition to hepatocytes, AAT is also synthesized by monocytes, neutrophils, and epithelial cells. In this study we show for the first time that the unfolded protein response (UPR) is activated in quiescent monocytes from ZZ individuals. Activating transcription factor 4, X-box binding protein 1, and a subset of genes involved in the UPR are increased in monocytes from ZZ compared with MM individuals. This contributes to an inflammatory phenotype with ZZ monocytes exhibiting enhanced cytokine production and activation of the NF-kappaB pathway when compared with MM monocytes. In addition, we demonstrate intracellular accumulation of AAT within the ER of ZZ monocytes. These are the first data showing that Z AAT protein accumulation induces UPR activation in peripheral blood monocytes. These findings change the current paradigm regarding lung inflammation in AAT deficiency, which up until now was derived from the protease-anti-protease hypothesis, but which now must include the exaggerated inflammatory response generated by accumulated aberrantly folded AAT in circulating blood cells.
- Alpha-1 antitrypsin Null mutations and severity of emphysema.
- Authors: Fregonese L, Stolk J, Frants RR, Veldhuisen B
- Issue date: 2008 Jun
- miR-199a-5p silencing regulates the unfolded protein response in chronic obstructive pulmonary disease and α1-antitrypsin deficiency.
- Authors: Hassan T, Carroll TP, Buckley PG, Cummins R, O'Neill SJ, McElvaney NG, Greene CM
- Issue date: 2014 Feb 1
- The discovery of α1-antitrypsin and its role in health and disease.
- Authors: Janciauskiene SM, Bals R, Koczulla R, Vogelmeier C, Köhnlein T, Welte T
- Issue date: 2011 Aug
- Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting.
- Issue date: 1997
- Regulator of G Signaling 16 is a marker for the distinct endoplasmic reticulum stress state associated with aggregated mutant alpha1-antitrypsin Z in the classical form of alpha1-antitrypsin deficiency.
- Authors: Hidvegi T, Mirnics K, Hale P, Ewing M, Beckett C, Perlmutter DH
- Issue date: 2007 Sep 21