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Fig. 9 | BMC Biology

Fig. 9

From: Loss of the interferon-γ-inducible regulatory immunity-related GTPase (IRG), Irgm1, causes activation of effector IRG proteins on lysosomes, damaging lysosomal function and predicting the dramatic susceptibility of Irgm1-deficient mice to infection

Fig. 9

Model for the cytopathic effects of dysregulated GKS proteins. a Regulatory immunity-related GTPase (IRG) GMS proteins localize to distinct cellular endomembranes including the endoplasmic reticulum (ER), Golgi, lipid droplets, and lysosomes and maintain effector IRG GKS proteins, which diffuse transiently onto these compartments, in an inactive GDP-bound state. b When T. gondii enters the host cell, GKS proteins diffuse onto this new membrane-bound compartment and activate at the parasitophorous vacuole membranes (PVM) because of the absence of GMS proteins. Activated GKS proteins form GTP-dependent oligomers and disrupt the membrane. c In Irgm1-deficient cells, lysosomal membranes lack any GMS proteins on the lysosomal membrane, allowing GKS proteins to activate and accumulate forming GTP-bound oligomers. Acidification of these lysosomes is impaired and with it lysosomal processing is not functional. These lysosomes cannot properly process autophagosomes after lysosome/autophagosome fusion. Hence, autophagic flux of IFN-γ-induced Irgm1 −/− cells is impaired. d In T. gondii-infected Irgm1 −/− cells, GKS proteins are accumulated at the lysosomes and therefore cannot properly accumulate and activate at the PVM. Disruption of the PVM does not happen and T. gondii can further proliferate. e In Irgm3-deficient cells it is the ER cisternae that are not protected by GMS proteins. Activated GKS proteins accumulate in local aggregates on the ER, possibly causing local ER deformation, but without such severe consequences for the cell as lysosomal impairment in Irgm1 −/− cells. f In T. gondii-infected Irgm3 −/− cells, GKS proteins are accumulated at the ER and therefore cannot properly accumulate and activate at the PVM. Disruption of the PVM does not happen and T. gondii can proliferate. g In Irgm1/Irgm3 −/− cells, lysosomes, ER, and lipid droplets are GMS-free. For unknown reasons, activated GMS proteins accumulate only at the lipid droplets and not at the other GMS-free compartments. h Upon T. gondii infection of Irgm1/Irgm3 −/− cells, GKS proteins activated at the lipid droplets cannot properly load to the PVM and inhibit T. gondii proliferation

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