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Leukocyte cell-derived chemotaxin 2 is an antiviral regulator acting through the proto-oncogene MET

Author

Listed:
  • Takayoshi Shirasaki

    (Kanazawa University Graduate School of Medical Science
    The University of North Carolina at Chapel Hill)

  • Satoshi Yamagoe

    (National Institute of Infectious Diseases)

  • Tetsuro Shimakami

    (Kanazawa University Graduate School of Medical Sciences)

  • Kazuhisa Murai

    (Kanazawa University Graduate School of Medical Science)

  • Ryu Imamura

    (Kanazawa University
    Kanazawa University)

  • Kiyo-Aki Ishii

    (Kanazawa University Graduate School of Medical Sciences)

  • Hiroaki Takayama

    (Kanazawa University Graduate School of Medical Sciences)

  • Yukako Matsumoto

    (Kanazawa University Graduate School of Medical Sciences)

  • Natsumi Tajima-Shirasaki

    (Kanazawa University Graduate School of Medical Sciences)

  • Naoto Nagata

    (Kanazawa University Graduate School of Medical Science)

  • Ryogo Shimizu

    (Kanazawa University Graduate School of Medical Science)

  • Souma Yamanaka

    (Kanazawa University Graduate School of Medical Science)

  • Atsushi Abe

    (Kanazawa University Graduate School of Medical Science)

  • Hitoshi Omura

    (Kanazawa University Graduate School of Medical Sciences)

  • Kazunori Kawaguchi

    (Kanazawa University Graduate School of Medical Sciences)

  • Hikari Okada

    (Kanazawa University Graduate School of Medical Sciences)

  • Taro Yamashita

    (Kanazawa University Graduate School of Medical Sciences)

  • Tomoki Yoshikawa

    (National Institute of Infectious Diseases)

  • Kazuhiro Takimoto

    (National Institute of Infectious Diseases)

  • Motoko Taharaguchi

    (National Institute of Infectious Diseases)

  • Shogo Takatsuka

    (National Institute of Infectious Diseases)

  • Yoshitsugu Miyazaki

    (National Institute of Infectious Diseases)

  • Toshikatsu Tamai

    (Kanazawa University Graduate School of Medical Science)

  • Yamato Tanabe

    (Kanazawa University Graduate School of Medical Science)

  • Makoto Kurachi

    (Kanazawa University Graduate School of Medical Science)

  • Yasuhiko Yamamoto

    (Kanazawa University Graduate School of Medical Science)

  • Shuichi Kaneko

    (Kanazawa University Graduate School of Medical Sciences)

  • Kunio Matsumoto

    (Kanazawa University
    Kanazawa University
    Kanazawa University)

  • Toshinari Takamura

    (Kanazawa University Graduate School of Medical Sciences)

  • Masao Honda

    (Kanazawa University Graduate School of Medical Science
    Kanazawa University Graduate School of Medical Sciences)

Abstract

Retinoic acid-inducible gene (RIG)-I is an essential innate immune sensor that recognises pathogen RNAs and induces interferon (IFN) production. However, little is known about how host proteins regulate RIG-I activation. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2), a hepatokine and ligand of the MET receptor tyrosine kinase is an antiviral regulator that promotes the RIG-I-mediated innate immune response. Upon binding to MET, LECT2 induces the recruitment of the phosphatase PTP4A1 to MET and facilitates the dissociation and dephosphorylation of phosphorylated SHP2 from MET, thereby protecting RIG-I from SHP2/c-Cbl-mediated degradation. In vivo, LECT2 overexpression enhances RIG-I-dependent IFN production and inhibits lymphocytic choriomeningitis virus (LCMV) replication in the liver, whereas these changes are reversed in LECT2 knockout mice. Forced suppression of MET abolishes IFN production and antiviral activity in vitro and in vivo. Interestingly, hepatocyte growth factor (HGF), an original MET ligand, inhibits LECT2-mediated anti-viral signalling; conversely, LECT2-MET signalling competes with HGF-MET signalling. Our findings reveal previously unrecognized crosstalk between MET-mediated proliferation and innate immunity and suggest that targeting LECT2 may have therapeutic value in infectious diseases and cancer.

Suggested Citation

  • Takayoshi Shirasaki & Satoshi Yamagoe & Tetsuro Shimakami & Kazuhisa Murai & Ryu Imamura & Kiyo-Aki Ishii & Hiroaki Takayama & Yukako Matsumoto & Natsumi Tajima-Shirasaki & Naoto Nagata & Ryogo Shimiz, 2022. "Leukocyte cell-derived chemotaxin 2 is an antiviral regulator acting through the proto-oncogene MET," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30879-3
    DOI: 10.1038/s41467-022-30879-3
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    References listed on IDEAS

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    1. Ying-Nan P. Chen & Matthew J. LaMarche & Ho Man Chan & Peter Fekkes & Jorge Garcia-Fortanet & Michael G. Acker & Brandon Antonakos & Christine Hiu-Tung Chen & Zhouliang Chen & Vesselina G. Cooke & Jas, 2016. "Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases," Nature, Nature, vol. 535(7610), pages 148-152, July.
    2. Yang Zhao & Xiang Ye & William Dunker & Yu Song & John Karijolich, 2018. "RIG-I like receptor sensing of host RNAs facilitates the cell-intrinsic immune response to KSHV infection," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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