Initial phospholipid-dependent Irgb6 targeting to<i>Toxoplasma gondii</i>vacuoles mediates host defense

Abstract

<i>Toxoplasma gondii</i> is an obligate intracellular protozoan parasite capable of infecting warm-blooded animals by ingestion. The organism enters host cells and resides in the cytoplasm in a membrane-bound parasitophorous vacuole (PV). Inducing an interferon response enables IFN-γ-inducible immunity-related GTPase (IRG protein) to accumulate on the PV and to restrict parasite growth. However, little is known about the mechanisms by which IRG proteins recognize and destroy <i>T. gondii</i> PV. We characterized the role of IRG protein Irgb6 in the cell-autonomous response against <i>T. gondii</i>, which involves vacuole ubiquitination and breakdown. We show that Irgb6 is capable of binding a specific phospholipid on the PV membrane. Furthermore, the absence of Irgb6 causes reduced targeting of other effector IRG proteins to the PV. This suggests that Irgb6 has a role as a pioneer in the process by which multiple IRG proteins access the PV. Irgb6-deficient mice are highly susceptible to infection by a strain of <i>T. gondii</i> avirulent in wild-type mice.