Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells
- UCL Institute of Child Health, United Kingdom
- University of Basel, Switzerland
- University of Cambridge, United Kingdom
- University Medical Centre Ljubljana, Slovenia
- 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
Adrian James Thrasher
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).
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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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
