Toxoplasma GRA 15 limits parasite growth in IFN γ‐activated fibroblasts through TRAF ubiquitin ligases

The protozoan parasite Toxoplasma gondii lives inside a vacuole in the host cytosol where it is protected from host cytoplasmic innate immune responses. However, IFN γ‐dependent cell‐autonomous immunity can destroy the vacuole and the parasite inside. Toxoplasma strain differences in susceptibility to human IFN γ exist, but the Toxoplasma effector(s) that determine these differences are unknown. We show that in human primary fibroblasts, the polymorphic Toxoplasma ‐secreted effector GRA 15 mediates the recruitment of ubiquitin ligases, including TRAF 2 and TRAF 6, to the vacuole membrane, which enhances recruitment of ubiquitin receptors (p62/ NDP 52) and ubiquitin‐like molecules ( LC 3B, GABARAP ). This ultimately leads to lysosomal degradation of the vacuole. In murine fibroblasts, GRA 15‐mediated TRAF 6 recruitment mediates the recruitment of immunity‐related GTP ases and destruction of the vacuole. Thus, we have identified how the Toxoplasma effector GRA 15 affects cell‐autonomous immunity in human and murine cells.