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Am J Physiol Gastrointest Liver Physiol 278: G39-G48, 2000;
0193-1857/00 $5.00
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Vol. 278, Issue 1, G39-G48, January 2000

Role of ubiquitin in proteasomal degradation of mutant alpha 1-antitrypsin Z in the endoplasmic reticulum

Jeffrey H. Teckman1,2, Reid Gilmore3, and David H. Perlmutter1,2,4

Departments of 1 Pediatrics and 4 Cell Biology and Physiology, Washington University School of Medicine, and 2 Division of Gastroenterology and Nutrition, Children's Hospital, St. Louis, Missouri 63110; and 3 Department of Biochemistry and Molecular Biology, University of Massachusetts, Boston, Massachusetts 01655

A delay in intracellular degradation of the mutant alpha 1-antitrypsin (alpha 1AT)Z molecule is associated with greater retention within the endoplasmic reticulum (ER) and susceptibility to liver disease in a subgroup of patients with alpha 1AT deficiency. Recent studies have shown that alpha 1ATZ is ordinarily degraded in the ER by a mechanism that involves the proteasome, as demonstrated in intact cells using human fibroblast cell lines engineered for expression of alpha 1ATZ and in a cell-free microsomal translocation assay system programmed with purified alpha 1ATZ mRNA. To determine whether the ubiquitin system is required for proteasomal degradation of alpha 1ATZ and whether specific components of the ubiquitin system can be implicated, we have now used two approaches. First, we overexpressed a dominant-negative ubiquitin mutant (UbK48R-G76A) by transient transfection in the human fibroblast cell lines expressing alpha 1ATZ. The results showed that there was marked, specific, and selective inhibition of alpha 1ATZ degradation mediated by UbK48R-G76A, indicating that the ubiquitin system is at least in part involved in ER degradation of alpha 1ATZ. Second, we subjected reticulocyte lysate to DE52 chromatography and tested the resulting well-characterized fractions in the cell-free system. The results showed that there were both ubiquitin-dependent and -independent proteasomal mechanisms for degradation of alpha 1ATZ and that the ubiquitin-conjugating enzyme E2-F1 may play a role in the ubiquitin-dependent proteasomal mechanism.

alpha 1-antitrypsin deficiency; liver disease; emphysema; quality- control apparatus; protein degradation; endoplasmic reticulum


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