Type

Journal Article

Authors

Noel G McElvaney
Shane J O'Neill
Aine M Nolan
Catherine A O'Connor
Catherine M Greene
Tomás P Carroll

Subjects

Biochemistry

Topics
blood monocytes male cells cultured biosynthesis pathology young adult amino acid substitution endoplasmic reticulum alpha 1 antitrypsin humans cytokines oxidative stress child gene expression regulation intracellular space female immunology alpha 1 antitrypsin deficiency genetics metabolism protein folding

Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency. (2010)

Abstract The 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.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Noel G McElvaney, Shane J O'Neill, Aine M Nolan, Catherine A O'Connor, Catherine M Greene, Tomás P Carroll

Experts in our system

1
Noel G McElvaney
Royal College of Surgeons in Ireland
Total Publications: 194
 
2
Shane J O'Neill
Royal College of Surgeons in Ireland
Total Publications: 84
 
3
Catherine M Greene
Royal College of Surgeons in Ireland
Total Publications: 150
 
4
Tomás P Carroll
Royal College of Surgeons in Ireland
Total Publications: 26