Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells

Pamela P. Lee, Damián Lobato-Márquez, Nayani Pramanik, Andrea Sirianni, Vanessa Daza-Cajigal, Elizabeth Rivers, Alessia Cavazza, Gerben Bouma, Dale Moulding, Kjell Hultenby, Lisa S. Westerberg, Michael Hollinshead, Yu-Lung Lau, Siobhan O. Burns, Serge Mostowy, Mona Bajaj-Elliott () and Adrian J. Thrasher ()
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Pamela P. Lee: Infection, Immunity and Inflammation Program, Great Ormond Street Institute of Child Health, University College London
Damián Lobato-Márquez: Section of Microbiology, MRC Centre of Molecular Bacteriology and Infection, Imperial College London
Nayani Pramanik: Infection, Immunity and Inflammation Program, Great Ormond Street Institute of Child Health, University College London
Andrea Sirianni: Section of Microbiology, MRC Centre of Molecular Bacteriology and Infection, Imperial College London
Vanessa Daza-Cajigal: University College London Institute of Immunity and Transplantation
Elizabeth Rivers: Infection, Immunity and Inflammation Program, Great Ormond Street Institute of Child Health, University College London
Alessia Cavazza: Infection, Immunity and Inflammation Program, Great Ormond Street Institute of Child Health, University College London
Gerben Bouma: Infection, Immunity and Inflammation Program, Great Ormond Street Institute of Child Health, University College London
Dale Moulding: Infection, Immunity and Inflammation Program, Great Ormond Street Institute of Child Health, University College London
Kjell Hultenby: Karolinska Institutet, Department of Laboratory Medicine
Lisa S. Westerberg: Karolinska Institutet, Department of Microbiology, Tumor and Cell Biology
Michael Hollinshead: University of Cambridge
Yu-Lung Lau: LKS Faculty of Medicine, The University of Hong Kong
Siobhan O. Burns: Infection, Immunity and Inflammation Program, Great Ormond Street Institute of Child Health, University College London
Serge Mostowy: Section of Microbiology, MRC Centre of Molecular Bacteriology and Infection, Imperial College London
Mona Bajaj-Elliott: Infection, Immunity and Inflammation Program, Great Ormond Street Institute of Child Health, University College London
Adrian J. Thrasher: Infection, Immunity and Inflammation Program, Great Ormond Street Institute of Child Health, University College London

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating inflammatory responses. Here we show that deficiency of Wiskott–Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. In a model of sterile inflammation utilizing TLR4 ligation followed by ATP or nigericin treatment, inflammasome activation is enhanced in monocytes from WAS patients and in WAS-knockout mouse dendritic cells. In ex vivo models of enteropathogenic Escherichia coli and Shigella flexneri infection, WASp deficiency causes defective bacterial clearance, excessive inflammasome activation and host cell death that are associated with dysregulated septin cage-like formation, impaired autophagic p62/LC3 recruitment and defective formation of canonical autophagosomes. Taken together, we propose that dysregulation of autophagy and inflammasome activities contribute to the autoinflammatory manifestations of WAS, thereby identifying potential targets for therapeutic intervention.

Date: 2017
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DOI: 10.1038/s41467-017-01676-0

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