1. Cell Biology
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Apolipoprotein L-1 renal risk variants form active channels at the plasma membrane driving cytotoxicity

  1. Joseph A Giovinazzo  Is a corresponding author
  2. Russell P Thomson
  3. Nailya Khalizova
  4. Patrick Zager
  5. Nirav Malani
  6. Enrique Javier Rodriguez-Boulan
  7. Jayne Raper  Is a corresponding author
  8. Ryan Schreiner  Is a corresponding author
  1. Hunter College of the City University of New York, United States
  2. Weill Cornell Medicine, United States
  3. Genosity, United States
Research Article
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Cite this article as: eLife 2020;9:e51185 doi: 10.7554/eLife.51185

Abstract

Recently evolved alleles of Apolipoprotein L-1 (APOL1) provide increased protection against African trypanosome parasites while also significantly increasing the risk of developing kidney disease in humans. APOL1 protects against trypanosome infections by forming ion channels within the parasite, causing lysis. While the correlation to kidney disease is robust, there is little consensus concerning the underlying disease mechanism. We show in human cells that the APOL1 renal risk variants have a population of active channels at the plasma membrane, which results in an influx of both Na+ and Ca2+. We propose a model wherein APOL1 channel activity is the upstream event causing cell death, and that the activate-state, plasma membrane-localized channel represents the ideal drug target to combat APOL1-mediated kidney disease.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures in Dryad.

The following data sets were generated

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Author details

  1. Joseph A Giovinazzo

    Department of Biological Sciences, Hunter College of the City University of New York, New York, United States
    For correspondence
    joseph.giovinazzo@cuanschutz.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Russell P Thomson

    Department of Biological Sciences, Hunter College of the City University of New York, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Nailya Khalizova

    Department of Biological Sciences, Hunter College of the City University of New York, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Patrick Zager

    Margaret Dyson Vision Research Institute, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3993-9686
  5. Nirav Malani

    Bioinformatics & Data Science, Genosity, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Enrique Javier Rodriguez-Boulan

    Dyson Vision Research Institute - Ophthalmology, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jayne Raper

    Department of Biological Sciences, Hunter College of the City University of New York, New York, United States
    For correspondence
    raper@genectr.hunter.cuny.edu
    Competing interests
    The authors declare that no competing interests exist.
  8. Ryan Schreiner

    Margaret Dyson Vision Research Institute, Weill Cornell Medicine, New York, United States
    For correspondence
    ryanschreiner@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7457-6606

Funding

National Institute of General Medical Sciences (R01GM34107)

  • Enrique Javier Rodriguez-Boulan

National Science Foundation (IOS-1249166)

  • Jayne Raper

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Christine Clayton, DKFZ-ZMBH Alliance, Germany

Publication history

  1. Received: August 19, 2019
  2. Accepted: May 14, 2020
  3. Accepted Manuscript published: May 19, 2020 (version 1)
  4. Version of Record published: June 12, 2020 (version 2)

Copyright

© 2020, Giovinazzo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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