title: Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens.
abstract: The physiologic importance of autophagy proteins for control of mammalian bacterial and parasitic infection in vivo is unknown. Using mice with granulocyte- and macrophage-specific deletion of the essential autophagy protein Atg5, we show that Atg5 is required for in vivo resistance to the intracellular pathogens Listeria monocytogenes and Toxoplasma gondii. In primary macrophages, Atg5 was required for interferongamma (IFN-gamma)/LPS-induced damage to the T. gondii parasitophorous vacuole membrane and parasite clearance. While we did not detect classical hallmarks of autophagy, such as autophagosomes enveloping T. gondii, Atg5 was required for recruitment of IFN-gamma-inducible p47 GTPase IIGP1 (Irga6) to the vacuole membrane, an event that mediates IFN-gamma-mediated clearance of T. gondii. This work shows that Atg5 expression in phagocytic cells is essential for cellular immunity to intracellular pathogens in vivo, and that an autophagy protein can participate in immunity and intracellular killing of pathogens via autophagosome-independent processes such as GTPase trafficking.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Zijiang
authors.initials: Z
authors.lastname: Zhao
authors.forename: Blima
authors.initials: B
authors.lastname: Fux
authors.forename: Megan
authors.initials: M
authors.lastname: Goodwin
authors.forename: Ildiko R
authors.initials: IR
authors.lastname: Dunay
authors.forename: David
authors.initials: D
authors.lastname: Strong
authors.forename: Brian C
authors.initials: BC
authors.lastname: Miller
authors.forename: Ken
authors.initials: K
authors.lastname: Cadwell
authors.forename: Monica A
authors.initials: MA
authors.lastname: Delgado
authors.forename: Marisa
authors.initials: M
authors.lastname: Ponpuak
authors.forename: Karen G
authors.initials: KG
authors.lastname: Green
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.forename: Vojo
authors.initials: V
authors.lastname: Deretic
authors.forename: L David
authors.initials: LD
authors.lastname: Sibley
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D002478:Cells, Cultured; D054884:Host-Pathogen Interactions; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000276:immunology; D008089:Listeria monocytogenes / Q000502:physiology*; D008088:Listeriosis / Q000276:immunology* / Q000382:microbiology; D008247:Lysosomes / Q000276:immunology / Q000469:parasitology; D008264:Macrophages / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D014122:Toxoplasma / Q000502:physiology*; D014123:Toxoplasmosis / Q000276:immunology* / Q000469:parasitology
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D007371:Interferon-gamma