A SNARE protective pool antagonizes APOL1 renal toxicity in Drosophila nephrocytes

• Published in: Cell & bioscience Vol. 13; no. 1; p. 199
• Main Authors: Lee, Jin-Gu, Fu, Yulong, Zhu, Jun-Yi, Wen, Pei, van de Leemput, Joyce, Ray, Patricio E, Han, Zhe
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 04.11.2023; BioMed Central; BMC
• Subjects: Antagonists; APOL1; Apolipoproteins; Chronic kidney failure; Cytotoxicity; Drosophila; Genes; Genetic aspects; Genetic engineering; Genetic screening; Genotype & phenotype; Insects; Kidney diseases; Nephrocytes; Protein binding; Proteins; Renal toxicity; Serum resistance-associated (SRA) protein; SNAP receptors; SNARE protective pool; SNARE proteins; Therapeutic targets; Toxicity; Serum resistance-associated (SRA) protein; Renal toxicity; APOL1; SNARE protective pool; SNARE proteins; Nephrocytes
• ISSN: 2045-3701; 2045-3701
• DOI: 10.1186/s13578-023-01147-8

People of Sub-Saharan African ancestry are at higher risk of developing chronic kidney disease (CKD), attributed to the Apolipoprotein L1 (APOL1) gene risk alleles (RA) G1 and G2. The underlying mechanisms by which the APOL1-RA precipitate CKD remain elusive, hindering the development of potential treatments. Using a Drosophila genetic modifier screen, we found that SNARE proteins (Syx7, Ykt6, and Syb) play an important role in preventing APOL1 cytotoxicity. Reducing the expression of these SNARE proteins significantly increased APOL1 cytotoxicity in fly nephrocytes, the equivalent of mammalian podocytes, whereas overexpression of Syx7, Ykt6, or Syb attenuated their toxicity in nephrocytes. These SNARE proteins bound to APOL1-G0 with higher affinity than APOL1-G1/G2, and attenuated APOL1-G0 cytotoxicity to a greater extent than either APOL1-RA. Using a Drosophila screen, we identified SNARE proteins (Syx7, Ykt6, and Syb) as antagonists of APOL1-induced cytotoxicity by directly binding APOL1. These data uncovered a new potential protective role for certain SNARE proteins in the pathogenesis of APOL1-CKD and provide novel therapeutic targets for APOL1-associated nephropathies.