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 α1-antitrypsin (α1AT) Z because retention of this mutant protein in the ER can cause severe target organ injury, the chronic hepatitis/hepatocellular carcinoma associated with α1AT deficiency. Here we examined the morphological changes that occur in human fibroblasts engineered for expression and ER retention of mutant α1ATZ and in human liver from three α1AT-deficient patients. In addition to marked expansion and dilatation of ER, there was an intense autophagic response. Mutant α1ATZ molecules were detected in autophagosomes by immune electron microscopy, and intracellular degradation of α1ATZ was partially reduced by chemical inhibitors of autophagy. In contrast to mutant CFTRΔF508, expression of mutant α1ATZ in heterologous cells did not result in the formation of aggresomes. These results show that ER retention of mutant α1ATZ is associated with a marked autophagic response and raise the possibility that autophagy represents a mechanism by which liver of α1AT-deficient patients attempts to protect itself from injury and carcinogenesis.

Teckman, J. H., & Perlmutter, D. H. (2000). Retention of mutant α1-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. American Journal of Physiology-Gastrointestinal and Liver Physiology, 279(5), G961–G974.