Guanylate binding proteins (GBPs) directly attack T. gondii via supramolecular complexes

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Abstract

GBPs are essential for immunity against intracellular pathogens, especially for T. gondii control. Here, the molecular interactions of murine GBPs (mGBP1/2/3/5/6), homo- and hetero-multimerization properties of mGBP2 and its function in parasite killing were investigated by mutational, Multiparameter Fluorescence Image Spectroscopy, and live cell microscopy methodologies. Control of T. gondii replication by mGBP2 requires GTP hydrolysis and isoprenylation thus, enabling reversible oligomerization in vesicle-like structures. mGBP2 undergoes structural transitions between monomeric, dimeric and oligomeric states visualized by quantitative FRET analysis. mGBPs reside in at least two discrete subcellular reservoirs and attack the parasitophorous vacuole membrane (PVM) as orchestrated, supramolecular complexes forming large, densely packed multimers comprising up to several thousand monomers. This dramatic mGBP enrichment results in the loss of PVM integrity, followed by a direct assault of mGBP2 upon the plasma membrane of the parasite. These discoveries provide vital dynamic and molecular perceptions into cell-autonomous immunity.

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Elisabeth Kravets

Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

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The authors declare that no competing interests exist.
Daniel Degrandi

Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

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The authors declare that no competing interests exist.
Qijun Ma

Institute for Molecular Physical Chemistry, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

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The authors declare that no competing interests exist.
Thomas-Otavio Peulen

Institute for Molecular Physical Chemistry, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

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The authors declare that no competing interests exist.
Verena Klümpers

Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany

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Suren Felekyan

Institute for Molecular Physical Chemistry, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

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Ralf Kühnemuth

Institute for Molecular Physical Chemistry, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

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Stefanie Weidtkamp-Peters

Center of Advanced Imaging, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

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Claus AM Seidel

Institute for Molecular Physical Chemistry, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

For correspondence
cseidel@hhu.de

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The authors declare that no competing interests exist.
Klaus Pfeffer

Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

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The authors declare that no competing interests exist.

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