ID: 165: Parasite control by cytokine-induced guanylate-binding proteins

Abstract

IFN γ is an immunomodulatory cytokine that rapidly activates potent host cell effector mechanisms to confront a variety of intracellular pathogens. Some of the most abundantly IFN γ induced proteins are the 65-kDa guanylate-binding proteins (GBPs), which mediate cell-autonomous immunity. GBPs are related to the dynamin super family of GTPases and are highly conserved throughout the vertebrate lineage. The human genome harbors seven GBPs and at least one pseudogene, whereas the mouse genome contains 11 GBPs and two pseudogenes. The gene loci of murine GBPs (mGBPs) are tandemly organized in clusters on chromosomes 3 and 5. GBPs contain a conserved GTPase-domain which binds guanine nucleotides with low affinities. This induces nucleotide dependent GBP multimerization and cooperative hydrolysis of GTP via GDP to GMP. Some GBPs are isoprenylated, endowing them with the ability to associate with intracellular membranous compartments. Murine GBPs (mGBPs) exert a major impact on cell-autonomous restriction of Toxoplasma gondii . T. gondii is an apicomplexan protozoan parasite with a broad host range, is distributed worldwide and causes serious and often fatal infections in immunocompromised hosts. T. gondii infection experiments in mice deficient for mGBP1 or mGBP2 prove that mGBPs are essential immune effector molecules mediating antiparasitic resistance. In several cell types distinct mGBPs accumulate at the parasitophorous vacuole membrane (PVM) of T. gondii . The translocation of mGBPs to the PVM is accompanied by depletion of cytosolic vesicle like structures (VLS), formation of large multimers at the PVM, subsequent loss of PVM integrity, followed by a direct assault of mGBP2 upon the plasma membrane of the parasite. These findings provide important dynamic and molecular insights into the function of cell-autonomous immunity.