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Am J Physiol Gastrointest Liver Physiol 279: G961-G974, 2000;
0193-1857/00 $5.00
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Vol. 279, Issue 5, G961-G974, November 2000

Retention of mutant alpha 1-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response

Jeffrey H. Teckman1 and David H. Perlmutter1,2

Departments of 1 Pediatrics and 2 Cell Biology and Physiology, Washington University School of Medicine, Division of Gastroenterology and Nutrition, St. Louis Children's Hospital, St. Louis, Missouri 63110

Although there is evidence for specific subcellular morphological alterations in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER), it is not clear whether these morphological changes are stereotypical or if they depend on the specific misfolded protein retained. This issue may be particularly important for mutant secretory protein alpha 1-antitrypsin (alpha 1AT) Z because retention of this mutant protein in the ER can cause severe target organ injury, the chronic hepatitis/hepatocellular carcinoma associated with alpha 1AT deficiency. Here we examined the morphological changes that occur in human fibroblasts engineered for expression and ER retention of mutant alpha 1ATZ and in human liver from three alpha 1AT-deficient patients. In addition to marked expansion and dilatation of ER, there was an intense autophagic response. Mutant alpha 1ATZ molecules were detected in autophagosomes by immune electron microscopy, and intracellular degradation of alpha 1ATZ was partially reduced by chemical inhibitors of autophagy. In contrast to mutant CFTRDelta F508, expression of mutant alpha 1ATZ in heterologous cells did not result in the formation of aggresomes. These results show that ER retention of mutant alpha 1ATZ is associated with a marked autophagic response and raise the possibility that autophagy represents a mechanism by which liver of alpha 1AT-deficient patients attempts to protect itself from injury and carcinogenesis.

autophagy; quality control; liver disease


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