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

J H Teckman1, D H Perlmutter

  • 1Department of Pediatrics, Washington University School of Medicine, Division of Gastroenterology and Nutrition, St. Louis Children's Hospital, St. Louis, Missouri 63110, USA. teckman@kids.wustl.edu

American Journal of Physiology. Gastrointestinal and Liver Physiology
|October 29, 2000
PubMed

Insights

Misfolded alpha(1)-antitrypsin Z protein triggers endoplasmic reticulum expansion and an autophagic response in liver cells. This autophagy may protect against injury and cancer in alpha(1)-antitrypsin deficiency.

Area of Science:

  • Cell Biology
  • Hepatology
  • Protein Misfolding Diseases

Background:

  • Accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes cellular stress and morphological changes.
  • The specific protein retained influences the cellular response, but this is not fully understood.
  • Mutant alpha(1)-antitrypsin Z (alpha(1)ATZ) retention in the ER is linked to liver injury and hepatocellular carcinoma in alpha(1)-antitrypsin deficiency.

Purpose of the Study:

  • To investigate the subcellular morphological alterations and cellular responses to ER-retained mutant alpha(1)ATZ.
  • To determine if the response to alpha(1)ATZ differs from other misfolded proteins like CFTRDeltaF508.
  • To explore the role of autophagy in mitigating ER stress and potential injury caused by alpha(1)ATZ.

Main Methods:

  • Studied human fibroblasts engineered for mutant alpha(1)ATZ expression and ER retention.
  • Examined liver tissue from alpha(1)-antitrypsin deficient patients.
  • Utilized immune electron microscopy to detect alpha(1)ATZ in autophagosomes.
  • Assessed the impact of autophagy inhibitors on intracellular alpha(1)ATZ degradation.

Main Results:

  • Observed significant ER expansion and dilatation in cells expressing mutant alpha(1)ATZ.
  • Detected an intense autophagic response, with mutant alpha(1)ATZ found within autophagosomes.
  • Inhibition of autophagy partially reduced intracellular alpha(1)ATZ degradation.
  • Mutant alpha(1)ATZ did not form aggresomes in heterologous cells, unlike mutant CFTRDeltaF508.

Conclusions:

  • ER retention of mutant alpha(1)ATZ induces a distinct autophagic response.
  • Autophagy may serve as a protective mechanism against liver injury and carcinogenesis in alpha(1)-antitrypsin deficiency.
  • The cellular response to misfolded proteins is protein-specific, influencing disease pathology.

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