Mechanisms underlying the cellular clearance of antitrypsin Z: lessons from yeast expression systems.

The most frequent cause of α(1)-antitrypsin (here referred to as AT) deficiency is homozygosity for the AT-Z allele, which encodes AT-Z. Such individuals are at increased risk for liver disease due to the accumulation of aggregation-prone AT-Z in the endoplasmic reticulum of hepatocytes. However, the penetrance and severity of liver dysfunction in AT deficiency is variable, indicating that unknown genetic and environmental factors contribute to its occurrence. There is evidence that the rate of AT-Z degradation may be one such contributing factor. Through the use of several AT-Z model systems, it is now becoming appreciated that AT-Z can be degraded through at least two independent pathways. One model system that has contributed significantly to our understanding of the AT-Z disposal pathway is the yeast, Saccharomyces cerevisiae.