Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 118, Issue 10, Pages 3090-3101Publisher
WILEY
DOI: 10.1002/jcb.26069
Keywords
ALPHA-1-ANTITRYPSIN; ERdj3; ER ASSOCIATED DEGRADATION; AUTOPHAGY
Categories
Funding
- Alpha-1 Foundation
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Alpha-1-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 amino acid 342 in the mature protein, resulting in the Z mutation of the alpha-1-antitrypsin gene (ZAAT). This substitution is associated with misfolding and accumulation of ZAAT in the endoplasmic reticulum(ER) of hepatocytes and monocytes, causing a toxic gain of function. Retained ZAAT is eliminated by ER-associated degradation and autophagy. We hypothesized that alpha-1-antitrypsin (AAT)-interacting proteins play critical roles in quality control of human AAT. Using co-immunoprecipitation, we identified ERdj3, an ER-resident Hsp40 family member, as a part of the AAT trafficking network. Depleting ERdj3 increased the rate of ZAAT degradation in hepatocytes by redirecting ZAAT to the ER calreticulin-EDEM1 pathway, followed by autophagosome formation. In the Huh7.5 cell line, ZAATER clearance resulted from enhancing ERdj3-mediated ZAAT degradation by silencing ERdj3 while simultaneously enhancing autophagy. In this context, ERdj3 suppression may eliminate the toxic gain of function associated with polymerization of ZAAT, thus providing a potential new therapeutic approach to the treatment of AATD-related liver disease. (C) 2017 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals Inc.
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