ArticleAmerican journal of physiology. Cell physiology2015
Exon 4-encoded sequence is a major determinant of cytotoxicity of apolipoprotein L1.
Article in American journal of physiology. Cell physiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 55 citations in OpenAlex.
- APOL1 plasma membrane pools resist rapid protein degradation.Scientific reports · 2026Article
- APOL1-mediated kidney disease: a narrative review of the lessons learnt from the past 15 years.BMC nephrology · 2025Review
- Article
- Review
- Pathogenesis of HIV-associated nephropathy in children and adolescents: taking a hard look 40 years later in the era of gene-environment interactions.American journal of physiology. Renal physiology · 2024Review
- Review
- IFI16 Is Indispensable for Promoting HIF-1α-Mediated APOL1 Expression in Human Podocytes under Hypoxic Conditions.International journal of molecular sciences · 2024Article
- Apolipoprotein L1 (APOL1) renal risk variant-mediated podocyte cytotoxicity depends on African haplotype and surface expression.Scientific reports · 2024Article
- A SNARE protective pool antagonizes APOL1 renal toxicity in Drosophila nephrocytes.Cell & bioscience · 2023Article
- Article
- Podocyte Endocytosis in Regulating the Glomerular Filtration Barrier.Frontiers in medicine · 2022Review
- Evolution of Renal-Disease Factor APOL1 Results in Cis and Trans Orientations at the Endoplasmic Reticulum That Both Show Cytotoxic Effects.Molecular biology and evolution · 2021Article
- The glomerular filtration barrier: a structural target for novel kidney therapies.Nature reviews. Drug discovery · 2021Review
- Apolipoprotein L1 and mechanisms of kidney disease susceptibility.Current opinion in nephrology and hypertension · 2021Review
- Lack of APOL1 in proximal tubules of normal human kidneys and proteinuric APOL1 transgenic mouse kidneys.PloS one · 2021Article
- The clinical significance of apolipoprotein L1 in head and neck squamous cell carcinoma.Oncology letters · 2020Article
- The Mechanism of Kidney Disease Due to APOL1 Risk Variants.Journal of the American Society of Nephrology : JASN · 2020Article
- Apolipoprotein L1-Specific Antibodies Detect Endogenous APOL1 inside the Endoplasmic Reticulum and on the Plasma Membrane of Podocytes.Journal of the American Society of Nephrology : JASN · 2020Article
- APOL1 renal risk variants exacerbate podocyte injury by increasing inflammatory stress.BMC nephrology · 2020Article
- APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin.Cell reports · 2020Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
The apolipoprotein L1 (APOL1) gene (APOL1) product is toxic to kidney cells, and its G1 and G2 alleles are strongly associated with increased risk for kidney disease progression in African Americans. Variable penetrance of the G1 and G2 risk alleles highlights the significance of additional factors that trigger or modify the progression of disease. In this regard, the effect of alternative splicing in the absence or presence of G1 or G2 alleles is unknown. In this study we investigated whether alternative splicing of non-G1, non-G2 APOL1 (APOL1 G0) affects its biological activity. Among seven APOL1 exons, exons 2 and 4 are differentially expressed in major transcripts. We found that, in contrast to APOL1 splice variants B3 or C, variants A and B1 demonstrate strong toxicity in human embryonic kidney (HEK293T) cells. Subsequently, we established that exon 4 is a major determinant of toxicity of variants A and B1 and that extracellular release of these variants is dispensable for their cytotoxicity. Although only variants A and B1 induced nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, exon 4-positive and -negative APOL1 variants stimulated perinuclear accumulation of unprocessed autophagosomes. Knockdown of endogenous TFEB did not attenuate APOL1 cytotoxicity, indicating that nuclear translocation of TFEB is dispensable for APOL1 toxicity. Our findings that a human podocyte cell line expresses exon 4-positive and -negative APOL1 transcripts suggest that these variants may play a differential role in podocyte pathology. In summary, we have identified exon 4 as a major determinant of APOL1 G0 cytotoxicity.
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