Lecture - Prof Dr Klaus Pfeffer - Interferon inducible guanylate binding proteins (GBPS) in immune defense

Host defense against invading pathogens is critically dependent upon interferon induced anti-microbial effector programs. Recently, we have discovered that vast number of interferon induced genes are GTPases belonging to the family of guanylate binding proteins (GBPs). GBPs are essential for immunity against intracellular pathogens, especially for Toxoplasma gondii control. Now 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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