NDLI: The ubiquitin ligase Hrd1 promotes degradation of the Z variant alpha 1-antitrypsin and increases its solubility

Content Provider	Springer Nature Link
Author	Wang, Haiping Li, Qi Shen, Yujun Sun, Aimin Zhu, Xiaoguang Fang, Shengyun Shen, Yuxian
Copyright Year	2010
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.
Starting Page	137
Ending Page	145
Page Count	9
File Format	PDF
ISSN	03008177
Journal	Molecular and Cellular Biochemistry
Volume Number	346
Issue Number	1-2
e-ISSN	15734919
Language	English
Publisher	Springer US
Publisher Date	2010-10-01
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Alpha 1-antitrypsin Z variant Hrd1 ER-associated degradation Ubiquitin–proteasome pathway Cardiology Oncology Medical Biochemistry Biochemistry
Content Type	Text
Resource Type	Article
Subject	Cell Biology Medicine Clinical Biochemistry Molecular Biology

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