Lectin–Like Ubiquitin Ligases Degrade Alpha‐1 Antitrypsin‐Z

Alpha‐1 antitrypsin deficiency is the leading cause of childhood liver failure, is responsible for two percent of all cases of emphysema in adults, and is one of the three most common lethal genetic diseases in Caucasians. The term A1AT‐Z deficiency is a misleading term; mutant A1AT‐Z fails to fold correctly and accumulates in the endoplasmic reticulum of the liver resulting in hepatic scarring, fibrosis, and carcinoma. The failure to correctly process the A1AT‐Z results in systemic deficiency leading to emphysema. The following study used cotransfection of mutant human A1At‐Z and ubiqtuin ligases into a variety of tissue culture cell lines. We identified three novel lectin‐like E3 ubiquitin ligases FBG1, FBG2, and FBG4 that participate in the clearance of A1AT‐Z. We demonstrate that both FBG1 and 2, but not FBG4, bind and pulldown A1AT‐Z. Only FBG1 and FBG2, are found in the liver, the location of A1AZ‐Z production. Furthermore, we show that soluble A1AT‐Z is degraded by the ubiquitin proteasome system and by autophagy while the insoluble form of A1AT‐Z is predominately degraded by autophagy. Overexpression of FBG1 and FBG2 decreases the half‐life of A1AT‐Z from 13 hours to 4 hours and 10 hours respectively. Finally, we show that FBG1 may increase A1AT‐Z secretion, suggesting that FBG1 may be used to treat both lung and liver disease in A1AT‐Z deficient patients.