Z α-1 antitrypsin deficiency and the endoplasmic reticulum stress response.
AffiliationCatherine M Greene, Noel G McElvaney, Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
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CitationZ α-1 antitrypsin deficiency and the endoplasmic reticulum stress response. 2010, 1 (5):94-101 World J Gastrointest Pharmacol Ther
JournalWorld journal of gastrointestinal pharmacology and therapeutics
AbstractThe serine proteinase inhibitor α-1 antitrypsin (AAT) is produced principally by the liver at the rate of 2 g/d. It is secreted into the circulation and provides an antiprotease protective screen throughout the body but most importantly in the lung, where it can neutralise the activity of the serine protease neutrophil elastase. Mutations leading to deficiency in AAT are associated with liver and lung disease. The most notable is the Z AAT mutation, which encodes a misfolded variant of the AAT protein in which the glutamic acid at position 342 is replaced by a lysine. More than 95% of all individuals with AAT deficiency carry at least one Z allele. ZAAT protein is not secreted effectively and accumulates intracellularly in the endoplasmic reticulum (ER) of hepatocytes and other AAT-producing cells. This results in a loss of function associated with decreased circulating and intrapulmonary levels of AAT. However, the misfolded protein acquires a toxic gain of function that impacts on the ER. A major function of the ER is to ensure correct protein folding. ZAAT interferes with this function and promotes ER stress responses and inflammation. Here the signalling pathways activated during ER stress in response to accumulation of ZAAT are described and therapeutic strategies that can potentially relieve ER stress are discussed.
- The role of proteases, endoplasmic reticulum stress and SERPINA1 heterozygosity in lung disease and α-1 anti-trypsin deficiency.
- Authors: Greene CM, Hassan T, Molloy K, McElvaney NG
- Issue date: 2011 Jun
- Selenoprotein S/SEPS1 modifies endoplasmic reticulum stress in Z variant alpha1-antitrypsin deficiency.
- Authors: Kelly E, Greene CM, Carroll TP, McElvaney NG, O'Neill SJ
- Issue date: 2009 Jun 19
- Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency.
- Authors: Carroll TP, Greene CM, O'Connor CA, Nolan AM, O'Neill SJ, McElvaney NG
- Issue date: 2010 Apr 15
- Tauroursodeoxycholic acid inhibits apoptosis induced by Z alpha-1 antitrypsin via inhibition of Bad.
- Authors: Miller SD, Greene CM, McLean C, Lawless MW, Taggart CC, O'Neill SJ, McElvaney NG
- Issue date: 2007 Aug
- 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