A06: Dynamics and trafficking of mGBP protein complexes within membranous compartments

Toxoplasma gondii parasites actively invade host cells by creating a specific membraneous subcellular compartment called the parasitophorous vacuole (PV). We have identified members of the mGBP (murine guanylate binding protein) family such as mGBP2 and mGBP7 that assemble at the cytoplasmatic site of the membrane of the PV. mGBP2 contains an N-terminal GTPase domain and a C-terminal isoprenylation motif that is essential for membrane interactions and biological functions whereas mGBP7 interacts with membrane compartments via a yet non-characterized mechanism. Interestingly, employing gene targeting in mice we have shown that mGBP2 and mGBP7 are essential for survival of T. gondii (ME49 strain) infections, where particularly the loss of mGBP7 leads to dramatic mortality comparable to IFNγR deficient mice. Thus, intersection of T. gondii parasites at their subcellular membrane interface by mGBPs is crucial for host defense.

The aim of this project will be the analysis of the molecular mechanisms by which mGBP2 and mGBP7 impair the vital functions of the membranes of the PV of T. gondii. Preliminary experiments have revealed, that mGBPs can build heteromers. Therefore, the molecular requirements and interactions of mGBP2 and mGBP7 with further members of the mGBP family will be investigated as well as the PV membrane associated molecular protein complexes will be identified. The molecular mechanisms of membrane targeting of mGBP2 and mGBP7 will be unraveled. Furthermore, it will be elucidated whether mGBP2 interacts directly with lipid components of the PV membrane of T. gondii. The project will yield insights into the dynamic biology of membrane systems at the interface of parasite and host.

Figure 1: Independent localization and function of GBP2 and mGBP7.

Project leaders: Dr. Daniel Degrandi, undefined email, and Prof. Dr. Klaus Pfeffer, undefined email,
                         undefinedInstitute of Medical Microbiology and Hospital Hygiene

Larissa Legewie, undefined email
                       Nora Steffens, undefined email

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