Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by early-onset emphysema and liver disease. The most common disease-causing mutation is a single amino acid substitution (Glu/Lys) at amino acid 342 of the mature protein, resulting in disruption of the 290-342 salt bridge (an electrophoretic abnormality defining the mutation [Z allele, or ZAAT]), protein misfolding, polymerization, and accumulation in the endoplasmic reticulum of hepatocytes and monocytes. The Z allele causes a toxic gain of function, and the E3 ubiquitin ligase gp78 promotes degradation and increased solubility of endogenous ZAAT. We hypothesized that the accumulation of ZAAT is influenced by modulation of gp78 E3 ligase and SVIP (small VCP-interacting protein) interaction with p97/VCP in ZAATexpressing hepatocytes. We showed that the SVIP inhibitory effect on ERAD due to overexpression causes the accumulation of ZAAT in a human Z hepatocyte-like cell line (AT01). Overexpression of gp78, as well as SVIP suppression, induces gp78-VCP/p97 interaction in AT01 cells. This interaction leads to retro-translocation of ZAAT and reduction of the SVIP inhibitory role in ERAD. In this context, overexpression of gp78 or SVIP 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.
Bibliographical noteFunding Information:
This work was supported by research grants from the Alpha-1 Foundation (www.alpha1. org) to MB and the Fundacion Leopoldo Fernandez. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The ultrastructural studies were conducted at the University of Florida College of Medicine Electron Microscopy Core Facility under the supervision of Dr. Jill Verlander, with the assistance of Dr. Sharon Matthews. This work was supported by research grants from the Alpha-1Foundation (www.alpha1.org) and the Fundacion Leopoldo Fernandez. Human tissue samples were obtained from the Alpha-1 Foundation DNA and Tissue Bank.
© 2017 Khodayari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.