Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells

  1. Elizabeth Rivers
  2. Rajeev Rai
  3. Jonas Lӧtscher
  4. Michael Hollinshead
  5. Gasper Markelj
  6. James Thaventheran
  7. Austen JJ Worth
  8. Alessia Cavazza
  9. Christopher Hess
  10. Mona Bajaj-Elliott
  11. Adrian James Thrasher  Is a corresponding author
  1. UCL Institute of Child Health, United Kingdom
  2. University of Basel, Switzerland
  3. University of Cambridge, United Kingdom
  4. University Medical Centre Ljubljana, Slovenia
  5. Great Ormond Street Hospital for Children NHS Foundation Trust, United Kingdom

Abstract

The actin cytoskeletal regulator Wiskott Aldrich syndrome protein (WASp) has been implicated in maintenance of the autophagy-inflammasome axis in innate murine immune cells. Here, we show that WASp deficiency is associated with impaired rapamycin-induced autophagosome formation and trafficking to lysosomes in primary human monocyte-derived macrophages (MDMs). WASp reconstitution in vitro and in WAS patients following clinical gene therapy restores autophagic flux and is dependent on the actin-related protein complex ARP2/3. Induction of mitochondrial damage with CCCP, as a model of selective autophagy, also reveals a novel ARP2/3-dependent role for WASp in formation of sequestrating actin cages and maintenance of mitochondrial network integrity. Furthermore, mitochondrial respiration is suppressed in WAS patient MDMs and unable to achieve normal maximal activity when stressed, indicating profound intrinsic metabolic dysfunction. Taken together, we provide evidence of new and important roles of human WASp in autophagic processes and immunometabolic regulation, which may mechanistically contribute to the complex WAS immunophenotype.

Data availability

All data associated with this study are present in this manuscript and Supporting Files.

Article and author information

Author details

  1. Elizabeth Rivers

    Infection, Immunity and Inflammation Programme, UCL Institute of Child Health, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Rajeev Rai

    Infection, Immunity and Inflammation Programme, UCL Institute of Child Health, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Jonas Lӧtscher

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Michael Hollinshead

    Department of Pathology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Gasper Markelj

    Department of Allergy, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
    Competing interests
    The authors declare that no competing interests exist.
  6. James Thaventheran

    Cambridge Institute for Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Austen JJ Worth

    Department of Immunology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6803-7385
  8. Alessia Cavazza

    Infection, Immunity and Inflammation Programme, UCL Institute of Child Health, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Christopher Hess

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  10. Mona Bajaj-Elliott

    Infection, Immunity and Inflammation Programme, UCL Institute of Child Health, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Adrian James Thrasher

    Infection, Immunity and Inflammation Programme, UCL Institute of Child Health, London, United Kingdom
    For correspondence
    a.thrasher@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6097-6115

Funding

Wellcome Trust (090233/Z/09/Z)

  • Adrian James Thrasher

Wellcome Trust (201250/Z/16/Z)

  • Elizabeth Rivers

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

Ethics

Human subjects: For usage of human CD34+ HSPC from healthy and WAS donors, informed written consent was obtained in accordance with the Declaration of Helsinki and ethical approval from the Great Ormond Street Hospital for Children NHS Foundation Trust and the Institute of Child Health Research Ethics (08/H0713/87).

Reviewing Editor

  1. Tiffany Horng, ShanghaiTech University, China

Publication history

  1. Received: January 28, 2020
  2. Accepted: October 31, 2020
  3. Accepted Manuscript published: November 2, 2020 (version 1)
  4. Version of Record published: November 18, 2020 (version 2)

Copyright

© 2020, Rivers 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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  1. Elizabeth Rivers
  2. Rajeev Rai
  3. Jonas Lӧtscher
  4. Michael Hollinshead
  5. Gasper Markelj
  6. James Thaventheran
  7. Austen JJ Worth
  8. Alessia Cavazza
  9. Christopher Hess
  10. Mona Bajaj-Elliott
  11. Adrian James Thrasher
(2020)
Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells
eLife 9:e55547.
https://doi.org/10.7554/eLife.55547
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