Alternative autophagy alleviates A1AT‐Z accrual (949.2)

Abstract

Alpha‐1 antitrypsin deficiency is the leading cause of childhood liver failure, one of the most common lethal genetic diseases, and is present in 1 in 2,500 people of European descent. The disease‐causing mutant A1AT‐Z fails to fold correctly and accumulates in the endoplasmic reticulum of the liver, resulting in hepatic fibrosis and hepatocellular carcinoma. A1AT‐Z sequestration in hepatocytes leads to reduced secretion, causing centrolobular emphysema in adults. The purpose of this work was to study the degradation of A1AT‐Z in hepatic tissue and cultured cell lines. We identified the ubiquitin ligase FBG1, which has been previously shown to degrade proteins by both the ubiquitin proteasome pathway and autophagy, as being key to A1AT‐Z degradation. Using chemical and genetic approaches we show that FBG1 degrades A1AT‐Z via both the ubiquitin proteasome system and autophagy. Overexpression of FBG1 decreases the half‐life of A1AT‐Z. Knocking down FBG1 in a hepatic cell line results in an increase in ATAT. Heterozygous A1AT‐Z mutant mice have more Periodic Acid Schiff Base positive inclusions in an FBG1 heterozygous knockdown background compared to mouse lines containing the full amount of FBG1. Finally, we show that FBG1 degrades A1AT‐Z through an ATG5‐independent arm of autophagy, suggesting that alternative autophagy may be important in treating A1AT‐Z deficiency.Grant Funding Source: VA‐Career Development Award