The ubiquitin ligase Hrd1 promotes degradation of the Z variant alpha 1-antitrypsin and increases its solubility View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2011-01

AUTHORS

Haiping Wang, Qi Li, Yujun Shen, Aimin Sun, Xiaoguang Zhu, Shengyun Fang, Yuxian Shen

ABSTRACT

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. More... »

PAGES

137-145

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s11010-010-0600-9

DOI

http://dx.doi.org/10.1007/s11010-010-0600-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1018031172

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20886262


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