Abstract
Cell-autonomous immunity to the bacterial pathogen Chlamydia trachomatis and the protozoan pathogen Toxoplasma gondii is controlled by two families of Interferon (IFN)-inducible GTPases: Immunity Related GTPases (IRGs) and Guanylate binding proteins (Gbps). Members of these two GTPase families associate with pathogen-containing vacuoles (PVs) and solicit antimicrobial resistance pathways specifically to the intracellular site of infection. The proper delivery of IRG and Gbp proteins to PVs requires the autophagy factor Atg5. Atg5 is part of a protein complex that facilitates the transfer of the ubiquitin-like protein Atg8 from the E2-like conjugation enzyme Atg3 to the lipid phosphatidylethanolamine. Here, we show that Atg3 expression, similar to Atg5 expression, is required for IRG and Gbp proteins to dock to PVs. We further demonstrate that expression of a dominant-active, GTP-locked IRG protein variant rescues the PV targeting defect of Atg3- and Atg5-deficient cells, suggesting a possible role for Atg proteins in the activation of IRG proteins. Lastly, we show that IFN-induced cell-autonomous resistance to C. trachomatis infections in mouse cells depends not only on Atg5 and IRG proteins, as previously demonstrated, but also requires the expression of Atg3 and Gbp proteins. These findings provide a foundation for a better understanding of IRG- and Gbp-dependent cell-autonomous resistance and its regulation by Atg proteins.
Highlights
Mammalian cells use an expansive network of cell-autonomous defense pathways to combat intracellular pathogens [1]
We found that colocalization of Irgb10 with T. gondii pathogen-containing vacuoles (PVs) mutant that is deficient of GTP binding
Because it was previously reported that Guanylate binding proteins (Gbps) proteins augment the colocalization of GKS proteins with T. gondii PVs [33], we explored whether Gbp proteins promote GKS protein association with C. trachomatis inclusions
Summary
Mammalian cells use an expansive network of cell-autonomous defense pathways to combat intracellular pathogens [1]. Similar to Gbp proteins, IRG proteins provide cell-autonomous immunity towards a subset of non-viral pathogens that include the protozoan Toxoplasma gondii and the bacterium Chlamydia trachomatis [4,8,9,10]. Both of these pathogens reside within vacuolar compartments known as a parasitophorous or pathogen-containing vacuoles, which we will refer to as PVs. Docking of IRG and Gbp proteins to PVs is essential to contain parasitic growth within IFN-activated cells [9,11,12,13]. Once recruited to PVs, IFN-inducible GTPases mediate the recruitment of antimicrobial defense modules that include, for example, components of the autophagic machinery [4]
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