Format

Send to

Choose Destination
PLoS Pathog. 2019 Feb 7;15(2):e1007551. doi: 10.1371/journal.ppat.1007551. eCollection 2019 Feb.

PIKfyve/Fab1 is required for efficient V-ATPase and hydrolase delivery to phagosomes, phagosomal killing, and restriction of Legionella infection.

Author information

1
Centre for Membrane Interactions and Dynamics, Department of Biomedical Sciences, University of Sheffield, Firth Court, Western Bank, Sheffield, United Kingdom.
2
Bateson Centre, University of Sheffield, Firth Court, Western Bank, Sheffield, United Kingdom.
3
Institute of Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
4
Department of Biochemistry, Faculty of Sciences, University of Geneva, Geneva, Switzerland.
5
Institute of Medical Microbiology, University of Zürich, Zürich, Switzerland.
6
School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
7
Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
8
CRUK Beatson Institute, Switchback Road, Bearsden, Glasgow, United Kingdom.

Abstract

By engulfing potentially harmful microbes, professional phagocytes are continually at risk from intracellular pathogens. To avoid becoming infected, the host must kill pathogens in the phagosome before they can escape or establish a survival niche. Here, we analyse the role of the phosphoinositide (PI) 5-kinase PIKfyve in phagosome maturation and killing, using the amoeba and model phagocyte Dictyostelium discoideum. PIKfyve plays important but poorly understood roles in vesicular trafficking by catalysing formation of the lipids phosphatidylinositol (3,5)-bisphosphate (PI(3,5)2) and phosphatidylinositol-5-phosphate (PI(5)P). Here we show that its activity is essential during early phagosome maturation in Dictyostelium. Disruption of PIKfyve inhibited delivery of both the vacuolar V-ATPase and proteases, dramatically reducing the ability of cells to acidify newly formed phagosomes and digest their contents. Consequently, PIKfyve- cells were unable to generate an effective antimicrobial environment and efficiently kill captured bacteria. Moreover, we demonstrate that cells lacking PIKfyve are more susceptible to infection by the intracellular pathogen Legionella pneumophila. We conclude that PIKfyve-catalysed phosphoinositide production plays a crucial and general role in ensuring early phagosomal maturation, protecting host cells from diverse pathogenic microbes.

PMID:
30730983
PMCID:
PMC6382210
DOI:
10.1371/journal.ppat.1007551
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center