A lag in intracellular degradation of mutant α1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ α1-antitrypsin deficiency

Ying Wu, Ina Whitman, Ernesto Molmenti, Kenneth Moore, Paul Hippenmeyer, David H. Perlmutter

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

Abstract

Liver injury in PiZZ α1-antitrypsin (α1-AT) deficiency probably results from toxic effects of the abnormal α1-AT molecule accumulating within the ER of liver cells. However, only 12-15% of individuals with this same genotype develops liver disease. Therefore, we predicted that other genetic traits that determine the net intracellular accumulation of the mutant α1-AT molecule would also determine susceptibility to liver disease. To address this prediction, we transduced skin fibroblasts from PiZZ individuals with liver disease or without liver disease with amphotropic recombinant retroviral particles designed for constitutive expression of the mutant α1-AT Z gene. Human skin fibroblasts do not express the endogenous α1-AT gene but presumably express other genes involved in postsynthetic processing of secretory proteins. The results show that expression of human α1-AT gene was conferred on each fibroblast cell line. Compared to the same cell line transduced with the wild-type α1-AT M gene, there was selective intracellular accumulation of the mutant α1-AT Z protein in each case. However, there was a marked delay in degradation of the mutant α1-AT Z protein after it accumulated in the fibroblasts from ZZ individuals with liver disease ('susceptible hosts') as compared to those without liver disease ('protected hosts'). Appropriate disease controls showed that the lag in degradation in susceptible hosts is specific for the combination of PiZZ phenotype and liver disease. Biochemical characteristics of α1-AT Z degradation in the protected hosts were found to be similar to those of a common ER degradation pathway previously described in model experimental cell systems for T-cell receptor α subunits and asialoglycoprotein receptor subunits, therefore, raising the possibility that the lag in degradation in the susceptible host is a defect in this common ER degradation pathway. Thus, these data provide evidence that other genetic traits that affect the fate of the abnormal α1-AT Z molecule, at least in part, determine susceptibility to liver disease. These data also validate a system for elucidating the biochemical/genetic characteristics of these traits and for examining the relevance to human disease of pathways for protein degradation in the ER.

Original languageEnglish
Pages (from-to)9014-9018
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number19
DOIs
StatePublished - Sep 13 1994

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