Biogenesis and cytotoxicity of APOL1 renal risk variant proteins in hepatocytes and hepatoma cells

摘要: Two APOL1 gene variants, which likely evolved to protect individuals from African sleeping sickness, are strongly associated with nondiabetic kidney disease in recent ancestry. Consistent its role trypanosome killing, the pro-death protein is toxic most cells, but mechanism of cell death poorly understood and little known regarding intracellular trafficking secretion. Because liver appears be main source circulating APOL1, we examined secretory behavior toxicity hepatoma cells primary human hepatocytes. secreted vitro, even presence chemical chaper­ones; however, it efficiently wild-type transgenic mice, suggesting that secretion has specialized requirements cultured fail support. In inducible expression risk variants promoted death, G1 variant displaying highest degree toxicity. To explore basis for APOL1-mediated toxicity, endoplasmic reticulum stress, pyroptosis, autophagy, apoptosis were examined. Our results suggest autophagy represents predominant death. Overall, these increase our understanding basic biology liver.