Role of ubiquitin in proteasomal degradation of mutant α1-antitrypsin Z in the endoplasmic reticulum

Jeffrey H. Teckman, Reid Gilmore, David H. Perlmutter

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A delay in intracellular degradation of the mutant α1-antitrypsin (α1AT)Z molecule is associated with greater retention within the endoplasmic reticulum (ER) and susceptibility to liver disease in a subgroup of patients with α1AT deficiency. Recent studies have shown that α1ATZ 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 α1ATZ and in a cell-free microsomal translocation assay system programmed with purified α1ATZ mRNA. To determine whether the ubiquitin system is required for proteasomal degradation of α1ATZ 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 α1ATZ. The results showed that there was marked, specific, and selective inhibition of α1ATZ degradation mediated by UbK48R-G76A, indicating that the ubiquitin system is at least in part involved in ER degradation of α1ATZ. 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 α1ATZ and that the ubiquitin-conjugating enzyme E2-F1 may play a role in the ubiquitin-dependent proteasomal mechanism.

Original languageEnglish
Pages (from-to)G39-G48
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number1 41-1
StatePublished - Jan 2000


  • Emphysema
  • Endoplasmic reticulum
  • Liver disease
  • Protein degradation
  • Quality-control apparatus
  • α-antitrypsin deficiency

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