title: Role of mouse and human autophagy proteins in IFN-γ-induced cell-autonomous responses against Toxoplasma gondii.
abstract: IFN-γ mediates cellular innate immunity against an intracellular parasite, Toxoplasma gondii, by inducing immunity-related GTPases such as p47 IFN-γ-regulated GTPases (IRGs) and p65 guanylate-binding proteins (GBPs), which also participate in antibacterial responses via autophagy. An essential autophagy protein, Atg5, was previously shown to play a critical role in anti-T. gondii cell-autonomous immunity. However, the involvement of other autophagy proteins remains unknown. In this study, we show that essential autophagy proteins differentially participate in anti-T. gondii cellular immunity by recruiting IFN-γ-inducible GTPases. IFN-γ-induced suppression of T. gondii proliferation and recruitment of an IRG Irgb6 and GBPs are profoundly impaired in Atg7- or Atg16L1-deficient cells. In contrast, cells lacking other essential autophagy proteins, Atg9a and Atg14, are capable of mediating the anti-T. gondii response and recruiting Irgb6 and GBPs to the parasites. Although IFN-γ also stimulates anti-T. gondii cellular immunity in humans, whether this response requires GBPs and human autophagy proteins remains to be seen. To analyze the role of human ATG16L1 and GBPs in IFN-γ-mediated anti-T. gondii responses, human cells lacking ATG16L1 or GBPs were generated by the Cas9/CRISPR genome-editing technique. Although both ATG16L1 and GBPs are dispensable for IFN-γ-induced inhibition of T. gondii proliferation in the human cells, human ATG16L1 is also required for the recruitment of GBPs. Taken together, human ATG16L1 and mouse autophagy components Atg7 and Atg16L1, but not Atg9a and Atg14, participate in the IFN-γ-induced recruitment of the immunity-related GTPases to the intracellular pathogen.
authors.affiliation: Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan;
authors.forename: Jun
authors.initials: J
authors.lastname: Ohshima
authors.forename: Youngae
authors.initials: Y
authors.lastname: Lee
authors.forename: Miwa
authors.initials: M
authors.lastname: Sasai
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Saitoh
authors.forename: Ji
authors.initials: J
authors.lastname: Su Ma
authors.forename: Naganori
authors.initials: N
authors.lastname: Kamiyama
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Matsuura
authors.forename: Suh
authors.initials: S
authors.lastname: Pann-Ghill
authors.forename: Mikako
authors.initials: M
authors.lastname: Hayashi
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Ebisu
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D001483:Base Sequence; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D055786:Gene Knockout Techniques; D006790:Host-Parasite Interactions / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D014122:Toxoplasma / Q000276:immunology* / Q000502:physiology; D014709:Vero Cells
chemical_list: C518959:ATG16L1 protein, human; C532820:Atg16l1 protein, mouse; C502661:Atg7 protein, mouse; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; D007371:Interferon-gamma; D000071193:Autophagy-Related Protein 7