A SNARE protective pool antagonizes APOL1 renal toxicity in Drosophila nephrocytes

Jin-Gu Lee; Yulong Fu; Jun-Yi Zhu; Pei Wen; Joyce van de Leemput; Patricio E Ray; Zhe Han

doi:10.1186/s13578-023-01147-8

A SNARE protective pool antagonizes APOL1 renal toxicity in Drosophila nephrocytes

Cell Biosci. 2023 Nov 4;13(1):199. doi: 10.1186/s13578-023-01147-8.

Authors

Jin-Gu Lee^#^{1

2}, Yulong Fu^#^{1

3}, Jun-Yi Zhu^#^{1

2}, Pei Wen^{1

2}, Joyce van de Leemput^{1

2}, Patricio E Ray⁴, Zhe Han^{5

6}

Affiliations

¹ Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine (UMSOM), 670 West Baltimore Street, 4052 HSFIII, Baltimore, MD, 21201, USA.
² Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
³ Department of Pathology, University of Alabama Birmingham, Birmingham, AL, 35249, USA.
⁴ Child Health Research Center, Department of Pediatrics, University of Virginia School of Medicine, 409 Lane Road, Charlottesville, VA, 22908, USA. Pray@virginia.edu.
⁵ Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine (UMSOM), 670 West Baltimore Street, 4052 HSFIII, Baltimore, MD, 21201, USA. zhan@som.umaryland.edu.
⁶ Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. zhan@som.umaryland.edu.

^# Contributed equally.

Abstract

Background: 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.

Results: 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.

Conclusions: 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.

Keywords: APOL1; Nephrocytes; Renal toxicity; SNARE protective pool; SNARE proteins; Serum resistance-associated (SRA) protein.

Abstract

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