The Atg5 Atg12 conjugate associates with innate antiviral immune responses.
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.
Jounai
Nao
N
Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Takeshita
Fumihiko
F
Kobiyama
Kouji
K
Sawano
Asako
A
Miyawaki
Atsushi
A
Xin
Ke-Qin
KQ
Ishii
Ken J
KJ
Kawai
Taro
T
Akira
Shizuo
S
Suzuki
Koichi
K
Okuda
Kenji
K
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
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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