Cell-autonomous Toxoplasma killing program requires Irgm2 but not its microbe vacuolar localization

Area of Science:

• Cellular and Molecular Immunology
• Host-Pathogen Interactions
• Innate Immunity

Background:

• Interferon-inducible GTPases, including IRGs and GBPs, are vital for cell-autonomous immunity against intracellular pathogens like Toxoplasma.
• Regulatory IRGs (Irgm1, Irgm3) control effector IRGs and GBPs, but the role of Irgm2, which localizes to Toxoplasma PVMs, remains unclear.

Purpose of the Study:

• To elucidate the mechanism of Irgm2's unique localization on Toxoplasma PVMs.
• To investigate the role of Irgm2 in anti-Toxoplasma immunity, including its dependence on PVM localization and ubiquitination.

Main Methods:

• Investigated Irgm2's role in parasite killing and effector recruitment (Gbp1, Irgb6).
• Analyzed the impact of Irgm2 ubiquitination (cytosolic vs. PVM) on effector recruitment.
• Examined PVM ubiquitination and p62/Sqstm1 loading in Irgm2-deficient mice and at later infection time points.
• Assessed susceptibility of Irgm2-deficient mice to Toxoplasma infection.

Main Results:

• Irgm2 is essential for parasite killing via Gbp1 and Irgb6 recruitment, independent of its PVM localization.
• Cytosolic Irgm2 ubiquitination is critical for Gbp1 recruitment to the PVM.
• PVM localization of Irgm2 is required for later PVM ubiquitination and p62/Sqstm1 loading.
• Irgm2-deficient mice exhibit high susceptibility to Toxoplasma infection.

Conclusions:

• Irgm2 selectively regulates the accumulation of anti-Toxoplasma effectors at the vacuole.
• Irgm2's function in parasite killing is mediated through both PVM-dependent and PVM-independent mechanisms.
• Irgm2 plays a critical, multifaceted role in host defense against Toxoplasma gondii.