The E2-like conjugation enzyme Atg3 promotes binding of IRG and Gbp proteins to Chlamydia- and Toxoplasma-containing vacuoles and host resistance

• Published in: PloS one Vol. 9; no. 1; p. e86684
• Main Authors: Haldar, Arun K, Piro, Anthony S, Pilla, Danielle M, Yamamoto, Masahiro, Coers, Jörn
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17-01-2014; Public Library of Science (PLoS)
• Subjects: Animals; Antimicrobial resistance; Autophagy; Autophagy-Related Protein 5; Autophagy-Related Proteins; Bacteria; Binding; Biological response modifiers; Biology; Cell death; Chlamydia; Chlamydia infections; Chlamydia Infections - immunology; Chlamydia Infections - metabolism; Chlamydia Infections - pathology; Chlamydia trachomatis; Chlamydia trachomatis - drug effects; Chlamydia trachomatis - metabolism; Chromosomes, Mammalian - metabolism; Conjugation; Defects; Disease Resistance - drug effects; Enzymes; G proteins; Genetics; GTP-Binding Proteins - metabolism; Guanosine triphosphatases; Guanosine triphosphate; Guanosine Triphosphate - metabolism; Health aspects; Immunity; Immunity - drug effects; Immunology; Inclusion Bodies - drug effects; Inclusion Bodies - metabolism; Infection; Infections; Interferon; Interferon-gamma - pharmacology; Medicine; Membranes; Mice; Microbial drug resistance; Microtubule-Associated Proteins - deficiency; Microtubule-Associated Proteins - metabolism; Mutant Proteins - metabolism; Pathogens; Phagocytosis; Phosphatidylethanolamine; Protein binding; Protein Binding - drug effects; Proteins; Protozoa; Recruitment; Rodents; Sexually transmitted diseases; STD; Toxoplasma - drug effects; Toxoplasma - metabolism; Toxoplasma gondii; Toxoplasmosis - immunology; Toxoplasmosis - metabolism; Toxoplasmosis - pathology; Ubiquitin; Ubiquitin-Conjugating Enzymes - deficiency; Ubiquitin-Conjugating Enzymes - metabolism; Vacuoles; Vacuoles - drug effects; Vacuoles - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0086684

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.