Modulation of calreticulin expression reveals a novel exosome-mediated mechanism of Z variant {alpha}1-antitrypsin disposal Cell Biology

α1-Antitrypsin deficiency (AATD) is an inherited disease characterized by emphysema and liver disease. AATD is most often caused by a single amino acid substitution at position 342 in the mature protein, resulting in the Z mutation of the AAT gene (ZAAT). This substitution is associated with misfolding and accumulation of ZAAT in the endoplasmic reticulum (ER) of hepatocytes, causing a toxic gain of function. ERdj3 is an ER luminal DnaJ homologue, which, along with calreticulin, directly interacts with misfolded ZAAT. We hypothesize that depletion of each of these chaperones will change the fate of ZAAT polymers. Our study demonstrates that calreticulin modulation reveals a novel ZAAT degradation mechanism mediated by exosomes. Using human PiZZ hepatocytes and K42, a mouse calreticulin-deficient fibroblast cell line, our results show ERdj3 and calreticulin directly interact with ZAAT in PiZZ hepatocytes. Silencing calreticulin induces calcium independent ZAAT–ERdj3 secretion through the exosome pathway. This co-secretion decreases ZAAT aggregates within the ER of hepatocytes. We demonstrate that calreticulin has an inhibitory effect on exosome-mediated ZAAT–ERdj3 secretion. This is a novel ZAAT degradation process that involves a DnaJ homologue chaperone bound to ZAAT. In this context, calreticulin modulation may eliminate the toxic gain of function associated with aggregation of ZAAT in lung and liver, thus providing a potential new therapeutic approach to ...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Cell Biology Source Type: research

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Authors: Pye A, Turner AM Abstract Introduction Alpha-1 antitrypsin deficiency (AATD) is most often associated with chronic lung disease, early onset emphysema and liver disease. The standard of care in lung disease due to AATD is alpha-1 antitrypsin augmentation but there are several new and emerging treatment options under investigation for both lung and liver manifestations. Areas covered We review therapeutic approaches to lung and liver disease in alpha-1 antitrypsin deficiency (AATD) and the agents in clinical development according to their mode of action. The focus is on products in clinical trials, but data...
Source: Expert Opinion on Investigational Drugs - Category: Drugs & Pharmacology Tags: Expert Opin Investig Drugs Source Type: research
Alpha-1 antitrypsin deficiency (AATD) is a common but under-recognised genetic condition that affects approximately 1 in 2000 to 1 in 5000 individuals and predisposes to early-onset emphysema and liver disease [1]. Alpha-1 antitrypsin (AAT) is mainly produced in the liver, and its main function is to protect the lung against proteolytic damage, especially from neutrophil elastase [2]. To date, more than 100 variant alleles of the AAT gene (SERPINA1) have been described, but the Z allele is the most prevalent and responsible for severe AATD leading to lung and liver disease [3].
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Editorials Source Type: research
Conclusions: Abnormal liver enzymes are frequent in carriers of the Z allele in AATD, but in the majority of cases this alteration does not translate to altered liver stiffness. Transient elastography could be a useful tool but validation with liver biopsy is needed.
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Clinical Problems Source Type: research
Conclusions: Genotypes associated with severe deficiency showed worse pulmonary function. Galicia is an area of relatively high prevalence of AATD, so this diagnostic possibility should be considered in the study of patients with diseases related to this genetic condition and in relatives of affected individuals.
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Clinical Problems Source Type: research
ConclusionsLung and liver transplantation in AATD patients are associated with very good long-term survival rates that are comparable to, and sometimes superior to, other transplant indications. Although not currently recommended in AATD, LVRS may have a role in a minority of patients. The value of Alpha 1 Antitrypsin (AAT) augmentation therapy following lung transplantation requires further study. Wherever possible, AAT therapy should be continued in the period around elective surgeries.SummaryAlthough AATD is a widely discussed and researched topic in the literature, surgical intervention for AATD, in addition to the man...
Source: The American Journal of Surgery - Category: Surgery Source Type: research
This study further underlines the importance of genotyping by whole SERPINA1 gene sequencing in addition to serum alpha-1 antitrypsin determination, to enable detection of alpha-1 antitrypsin deficiency due to rare genotypes.
Source: Respiratory Medicine Case Reports - Category: Respiratory Medicine Source Type: research
Authors: Patrucco F, Venezia L, Gavelli F, Pellicano R, Solidoro P Abstract Alpha-1 antitrypsin deficiency (AATD) is a clinically under-recognized inherited disorder affecting the lungs and the liver. The most common manifestations are pulmonary emphysema, bronchiectasis and liver disease. The recent publication of the European Respiratory Society statement on diagnosis and treatment of pulmonary diseases has replaced the 2003 American Thoracic Society and European Respiratory Society one. New outcome parameters have been introduced and validated by observational and randomized clinical trials, and new information ...
Source: Panminerva Medica - Category: General Medicine Tags: Panminerva Med Source Type: research
This study further underlines the importance of genotyping by whole SERPINA1 gene sequencing in addition to serum alpha-1 antitrypsin determination, to enable detection of alpha-1 antitrypsin deficiency due to rare genotypes.
Source: Respiratory Medicine Case Reports - Category: Respiratory Medicine Source Type: research
Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant disease which predisposes patients to early-onset emphysema and liver cirrhosis.1 Estimates of the number of adult patients with AATD exhibiting clinically significant liver disease have varied from 10% (defined by aminotransferase abnormalities)2,3 to 18% in a UK cohort assessed by ultrasound (+/ − biopsy)4 to approximately 35% in those with an Ishak fibrosis score ≥2 assessed histologically after liver biopsy.5 A Swedish autopsy series from patients with AATD and the PiZZ genotype found liver disease to be present in the majority of patients, albe...
Source: Journal of Hepatology - Category: Gastroenterology Authors: Tags: Research Article Source Type: research
Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant disease which predisposes to early-onset emphysema and liver cirrhosis [1]. Estimates of the number of adult AATD patients exhibiting clinically significant liver disease have varied from 10% (defined by transaminase abnormalities) [2,3] to 18% in a U.K. cohort assessed by ultrasound (+/- biopsy) [4] to approximately 35% in those with an Ishak fibrosis score ≥ 2 assessed histologically after liver biopsy [5]. A Swedish autopsy series from AATD patients with the PiZZ genotype found liver disease to be present in the majority of patients, albeit unrecognize...
Source: Journal of Hepatology - Category: Gastroenterology Authors: Source Type: research
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