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

Takayoshi Shirasaki (), Satoshi Yamagoe, Tetsuro Shimakami, Kazuhisa Murai, Ryu Imamura, Kiyo-Aki Ishii, Hiroaki Takayama, Yukako Matsumoto, Natsumi Tajima-Shirasaki, Naoto Nagata, Ryogo Shimizu, Souma Yamanaka, Atsushi Abe, Hitoshi Omura, Kazunori Kawaguchi, Hikari Okada, Taro Yamashita, Tomoki Yoshikawa, Kazuhiro Takimoto, Motoko Taharaguchi, Shogo Takatsuka, Yoshitsugu Miyazaki, Toshikatsu Tamai, Yamato Tanabe, Makoto Kurachi, Yasuhiko Yamamoto, Shuichi Kaneko, Kunio Matsumoto, Toshinari Takamura and Masao Honda ()
Additional contact information
Takayoshi Shirasaki: Kanazawa University Graduate School of Medical Science
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
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
Toshinari Takamura: Kanazawa University Graduate School of Medical Sciences
Masao Honda: Kanazawa University Graduate School of Medical Science

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30879-3

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