Immunity-related GTPases (IRGs) specifically localize to and destroy pathogen-containing vacuoles (PVs).
•IRGs must differentiate PV membranes from host membranes.
•We present a three-signal model for IRG recruitment to PVs.
•Lipidated Atg8 and the absence of host IRG-clade M are two signals for IRG recruitment.
•IRGs may specifically bind lipid species enriched on PVs, comprising a third signal.
The cytokine gamma-interferon activates cell-autonomous immunity against intracellular bacterial and protozoan pathogens by inducing a slew of antimicrobial proteins, some of which hinge upon immunity-related GTPases (IRGs) for their function. Three regulatory IRG clade M (Irgm) proteins chaperone about approximately 20 effector IRGs (GKS IRGs) to localize to pathogen-containing vacuoles (PVs) within mouse cells, initiating a cascade that results in PV elimination and killing of PV-resident pathogens. However, the mechanisms that allow IRGs to identify and traffic specifically to ‘non-self’ PVs have remained elusive. Integrating recent findings demonstrating direct interactions between GKS IRGs and lipids with previous work, we propose that three attributes mark PVs as GKS IRG targets: the absence of membrane-bound Irgm proteins, Atg8 lipidation, and the presence of specific lipid species. Combinatorial recognition of these three distinct signals may have evolved as a mechanism to ensure safe delivery of potent host antimicrobial effectors exclusively to PVs.
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