title: Biogenesis and cytotoxicity of APOL1 renal risk variant proteins in hepatocytes and hepatoma cells.
abstract: Two APOL1 gene variants, which likely evolved to protect individuals from African sleeping sickness, are strongly associated with nondiabetic kidney disease in individuals with recent African ancestry. Consistent with its role in trypanosome killing, the pro-death APOL1 protein is toxic to most cells, but its mechanism of cell death is poorly understood and little is known regarding its intracellular trafficking and secretion. Because the liver appears to be the main source of circulating APOL1, we examined its secretory behavior and mechanism of toxicity in hepatoma cells and primary human hepatocytes. APOL1 is poorly secreted in vitro, even in the presence of chemical chaper-ones; however, it is efficiently secreted in wild-type transgenic mice, suggesting that APOL1 secretion has specialized requirements that cultured cells fail to support. In hepatoma cells, inducible expression of APOL1 and its risk variants promoted cell death, with the G1 variant displaying the highest degree of toxicity. To explore the basis for APOL1-mediated cell toxicity, endoplasmic reticulum stress, pyroptosis, autophagy, and apoptosis were examined. Our results suggest that autophagy represents the predominant mechanism of APOL1-mediated cell death. Overall, these results increase our understanding of the basic biology and trafficking behavior of circulating APOL1 from the liver.
authors.affiliation: Department of Internal Medicine, Sections on Molecular Medicine Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Department of Internal Medicine, Sections on Molecular Medicine Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Allison
authors.initials: A
authors.lastname: Weckerle
authors.affiliation: Department of Internal Medicine, Sections on Molecular Medicine Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Nephrology, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Lijun
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Internal Medicine, Sections on Molecular Medicine Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Nephrology, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Mariana
authors.initials: M
authors.lastname: Murea
authors.affiliation: Nephrology, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Department of Internal Medicine, Sections on Molecular Medicine Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.affiliation: Department of Internal Medicine, Sections on Molecular Medicine Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Shelness
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001343:Autophagy; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008075:Lipoproteins, HDL / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D000069292:Pyroptosis; D051381:Rats
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL; D046988:Proteasome Endopeptidase Complex
keywords: apolipoprotein L1; apolipoproteins; apoptosis; endoplasmic reticulum; liver