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PNAS 104 (35): 14050-14055

Copyright © 2007 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / IMMUNOLOGY

The Atg5–Atg12 conjugate associates with innate antiviral immune responses

Nao Jounai*, Fumihiko Takeshita*,{dagger}, Kouji Kobiyama*, Asako Sawano{ddagger}, Atsushi Miyawaki{ddagger}, Ke-Qin Xin*, Ken J. Ishii§,¶, Taro Kawai§,||, Shizuo Akira§,||, Koichi Suzuki**, and Kenji Okuda*

*Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; {ddagger}Laboratory for Cell Function Dynamics, Advanced Technology Development Group, Brain Science Institute, Institute of Physical and Chemical Research (RIKEN), Saitama 351-0198, Japan; §Exploratory Research for Advanced Technology, Akira Innate Immunity Program, Japan Science and Technology Agency, Osaka 565-0871, Japan; Departments of Molecular Protozoology and ||Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; and **Department of Bioregulation, Leprosy Research Center, National Institute of Infectious Diseases, Tokyo 189-0002, Japan

Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved July 11, 2007

Received for publication May 1, 2007.

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.

Key Words: innate immunity • signal transduction • type I interferon

Author contributions: N.J. and F.T. contributed equally to this work; N.J., F.T., A.M., T.K., S.A., and K.O. designed research; N.J., F.T., K.K., A.S., and K.J.I. performed research; N.J., K.K., A.S., and K.J.I. analyzed data; and N.J., F.T., K.-Q.X., and K.S. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0704014104/DC1.

{dagger}To whom correspondence should be addressed at: Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawaku, Yokohama 236-0004, Japan. E-mail: takesita{at}yokohama-cu.ac.jp

© 2007 by The National Academy of Sciences of the USA

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