Retention of mutant α₁-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response

Abstract

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(1)AT) Z because retention of this mutant protein in the ER can cause severe target organ injury, the chronic hepatitis/hepatocellular carcinoma associated with alpha(1)AT deficiency. Here we examined the morphological changes that occur in human fibroblasts engineered for expression 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 dilatation of ER, there was an intense autophagic response. Mutant alpha(1)ATZ molecules 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 CFTRDeltaF508, expression of mutant alpha(1)ATZ in heterologous cells did not result in the formation of aggresomes. These results show that ER retention of mutant alpha(1)ATZ is associated with a marked autophagic response and raise the possibility that autophagy represents a mechanism by which liver of alpha(1)AT-deficient patients attempts to protect itself from injury and carcinogenesis.

Alpha-1-Antitrypsin Deficiency: A New Paradigm for Hepatocellular Carcinoma in Genetic Liver Disease *

“…19 Cabral et al 23 have provided evidence for a nonproteosomal degradation pathway that is sensitive to tyrosine phosphatase inhibitors. We have shown that macroautophagy contributes to disposal of retained ␣1ATZ, using chemical inhibitors 24 and cell lines genetically engineered for deficient autophagy (unpublished observations). Macroautophagy is a general stress-activated degradative mechanism whereby cytosol and intracellular organelles, such as mitochondria and parts of the ER, are first sequestered away from the rest of the cytoplasm into doublemembrane vesicles and then the vesicles fuse with the lysosome for degradation of the vesicles and their constituents (Fig.…”

The pleiotropic role of autophagy: from protein metabolism to bactericide

“…16,17 Inhibition of autophagy induces aggregate formation, whereas rapamycin-induced upregulation of autophagy reduces it. [18][19][20][21] Furthermore, amelioration of neurodegeneration and improvement of behavior were reported in a D. melanogaster Huntington model following treatment with a rapamycin analog, CCI-779. 21 It has been speculated that aggregates can be degraded by autophagy Figure 2 Molecular mechanism of autophagy regulation and autophagosome formation.…”

Autophagy at the crossroads of catabolism and anabolism

“…Autophagy selectively degrades aggregated proteins that accumulate in the ER lumen, such as the mutant secretory protein α1-antitrypsin 121 . Additionally, studies of yeast and mammalian cells demonstrate that autophagy mediates ER homeostasis by selectively segregating portions of this organelle network; this process has been termed ER-phagy or reticulophagy [122][123][124][125] .…”