Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies of the ubiquitin-proteasome system in alpha1-antitrypsin (AAT) deficiency have been performed using only biochemical and molecular biology techniques on human cells as well as on AAT-deficient transduced cell lines. The objective of our study was to assess the immunohistochemical and topographic features of ubiquitin in the livers of AAT-deficient children with and without active liver disease. Fourteen cases of AAT deficiency were retrieved from our archives, along with 10 control liver specimens obtained from autopsies of age-matched children with no clinical, gross anatomic, or histologic evidence of liver disease. Twelve of 14 cases of AAT deficiency were cirrhotic explanted livers from transplantations procedures. Two cases were noncirrhotic liver biopsies from asymptomatic patients. Periodic acid-Schiff (PAS) histochemistry and AAT immunostains were performed on all AAT-deficient liver specimens to verify the diagnosis. Immunohistochemistry with polyclonal ubiquitin antibodies was performed on all specimens. Ubiquitin immunoreactivity was present in all AAT livers while control livers were consistently negative or weakly reactive. In cirrhotic livers, ubiquitin immunoreactivity was strongest in the cytoplasm whereas the characteristic PAS-positive, diastase-resistant cytoplasmic granules appeared nonreactive. However, not all cirrhotic livers showed this pattern. Some were only focally positive (<5% of hepatocytes). In asymptomatic patients, ubiquitin staining was diffuse and moderate to prominent, and evenly distributed within individual hepatocytes and lobules. We therefore conclude that the ubiquitin-proteasome pathway is operative in the hepatocytes of AAT-deficient livers, as illustrated by the study of ubiquitin immunoreactivity. However, some AAT-deficient livers are only focally immunoreactive for ubiquitin. This may indicate an intrinsic defect of the ubiquitin-proteasome system in some patients.
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PMID:Hepatocellular ubiquitin expression in alpha1-antitrypsin deficiency. 1144 35

Alpha 1-antitrypsin (AAT) deficiency is an autosomal recessive disorder that is characterized by the retention of misfolded AAT in the endoplasmic reticulum (ER) of hepatocytes and a significant decrease in the serum levels of AAT. Previous studies have demonstrated that the ubiquitin-proteasome pathway is involved in the degradation of the Z variant of AAT (ATZ). However, the detailed mechanisms of ATZ degradation are not fully understood. We investigated whether the ER membrane-embedded ubiquitin ligase (E3) Hrd1 promotes the removal of ATZ through ER-associated degradation (ERAD). Our results indicate that Hrd1 decreases intracellular levels of ATZ, especially the detergent-insoluble fraction, in cells transfected with a plasmid-encoding ATZ. The degradation of ATZ was also found to be dependent on the functional E3 activity of Hrd1. In addition, we demonstrated that Hrd1 increases the solubility of ATZ. Cycloheximide (CHX) chase and proteasome inhibition experiments showed that the ubiquitin-proteasome pathway is involved in Hrd1-mediated ATZ degradation. Furthermore, we found that Hrd1 helped to maintain normal morphology of ATZ expressing cells. These data indicate that Hrd1 enhances the removal of ATZ through ERAD and attenuates intracellular ATZ accumulation and toxicity, which implies a potential value for Hrd1 in the treatment of AAT deficiency diseases.
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PMID:The ubiquitin ligase Hrd1 promotes degradation of the Z variant alpha 1-antitrypsin and increases its solubility. 2088 62