The Atg5–Atg12 conjugate associates with innate antiviral immune responses

N Jounai, F Takeshita, K Kobiyama… - Proceedings of the …, 2007 - National Acad Sciences
N Jounai, F Takeshita, K Kobiyama, A Sawano, A Miyawaki, KQ Xin, KJ Ishii, T Kawai…
Proceedings of the National Academy of Sciences, 2007National Acad Sciences
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 …
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-β 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.
National Acad Sciences