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

Although there is evidence for specific subcellular morphological alteratio ns in response to accumulation of misfolded proteins in the endoplasmic ret iculum (ER), it is not clear whether these morphological changes are stereo typical or if they depend on the specific misfolded protein retained. This issue may be particularly important for mutant secretory protein alpha (1)- antitrypsin (alpha (1)AT) Z because retention of this mutant protein in the ER can cause severe target organ injury, the chronic hepatitis/hepatocellu lar carcinoma associated with alpha (1)AT deficiency. Here we examined the morphological changes that occur in human fibroblasts engineered for expres sion and ER retention of mutant alpha (1)ATZ and in human liver from three alpha (1)AT-deficient patients. In addition to marked expansion and dilatat ion of ER, there was an intense autophagic response. Mutant alpha (1)ATZ mo lecules were detected in autophagosomes by immune electron microscopy, and intracellular degradation of alpha (1)ATZ was partially reduced by chemical inhibitors of autophagy. In contrast to mutant CFTR Delta F508, expression of mutant alpha (1)ATZ in heterologous cells did not result in the formati on 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 (1)AT-deficie nt patients attempts to protect itself from injury and carcinogenesis.