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1-antitrypsin Z in
endoplasmic reticulum is associated with an autophagic
response
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 
1-antitrypsin (1AT) Z because retention of this mutant protein in the ER can cause severe target organ injury, the chronic hepatitis/hepatocellular carcinoma associated with 1AT deficiency. Here we examined the
morphological changes that occur in human fibroblasts engineered for
expression and ER retention of mutant 1ATZ and in human
liver from three 1AT-deficient patients. In addition to
marked expansion and dilatation of ER, there was an intense autophagic
response. Mutant 1ATZ molecules were detected in
autophagosomes by immune electron microscopy, and intracellular
degradation of 1ATZ was partially reduced by chemical
inhibitors of autophagy. In contrast to mutant CFTR
F508, expression
of mutant 1ATZ in heterologous cells did not result in
the formation of aggresomes. These results show that ER retention of
mutant 1ATZ is associated with a marked autophagic
response and raise the possibility that autophagy represents a
mechanism by which liver of 1AT-deficient patients
attempts to protect itself from injury and carcinogenesis.
autophagy; quality control; liver disease
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