title: The Atg5 Atg12 conjugate associates with innate antiviral immune responses.
abstract: Autophagy is an essential process for physiological homeostasis, but its role in viral infection is only beginning to be elucidated. We show here that the Atg5-Atg12 conjugate, a key regulator of the autophagic process, plays an important role in innate antiviral immune responses. Atg5-deficient mouse embryonic fibroblasts (MEFs) were resistant to vesicular stomatitis virus replication, which was largely due to hyperproduction of type I interferons in response to immunostimulatory RNA (isRNA), such as virus-derived, double-stranded, or 5'-phosphorylated RNA. Similar hyperresponse to isRNA was also observed in Atg7-deficient MEFs, in which Atg5-Atg12 conjugation is impaired. Overexpression of Atg5 or Atg12 resulted in Atg5-Atg12 conjugate formation and suppression of isRNA-mediated signaling. Molecular interaction studies indicated that the Atg5-Atg12 conjugate negatively regulates the type I IFN production pathway by direct association with the retinoic acid-inducible gene I (RIG-I) and IFN-beta promoter stimulator 1 (IPS-1) through the caspase recruitment domains (CARDs). Thus, in contrast to its role in promoting the bactericidal process, a component of the autophagic machinery appears to block innate antiviral immune responses, thereby contributing to RNA virus replication in host cells.
authors: Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors: Nao
authors: N
authors: Jounai
authors: Fumihiko
authors: F
authors: Takeshita
authors: Kouji
authors: K
authors: Kobiyama
authors: Asako
authors: A
authors: Sawano
authors: Atsushi
authors: A
authors: Miyawaki
authors: Ke-Qin
authors: KQ
authors: Xin
authors: Ken J
authors: KJ
authors: Ishii
authors: Taro
authors: T
authors: Kawai
authors: Shizuo
authors: S
authors: Akira
authors: Koichi
authors: K
authors: Suzuki
authors: Kenji
authors: K
authors: Okuda
mesh_terms: D000818:Animals; D001343:Autophagy; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D002478:Cells, Cultured; D005347:Fibroblasts / Q000502:physiology; D017930:Genes, Reporter; D007113:Immunity, Innate; D007370:Interferon Type I / Q000235:genetics; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000276:immunology*; D012330:RNA, Double-Stranded / Q000235:genetics; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D014779:Virus Replication
chemical_list: C491971:Atg12 protein, mouse; C495773:Atg5 protein, mouse; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D007370:Interferon Type I; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D011506:Proteins; D012330:RNA, Double-Stranded
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