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

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.


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No data were excluded from the analyses.
Data reproducibility was confirmed in multiple independent experiments as described in legends.
For in vitro experiments, samples were randomly assigned. For in vivo experiments, Age-and sex-matched wild-type, Lect2-TG and Lect2-KO mice were randomly allocated.
The investigators were blinded during the experiments, and during which only numbers were used to define samples.
Cell lines were confirmed by immunoblotting of proteins and RTD-PCR of gene expression.
Cell lines were tested for mycoplasma contamination by a PCR-based method and found to be negative.
No commonly misidentified cell lines were used in this study.
6-8 week old, male, wild type C57BL/6, Lect2-TG and Lect2-KO mice were used in this study. The mice were kept in a controlled environment with 40% humidity, 20°C temperature conditions and 12h light-and-dark cycles, and were accessible at all times to water and food. All mice were bred and kept under specific pathogen-free conditions.
No wild animals were used in this study.
The study did not involve field-collected samples.
All mouse studies were carried out in accordance with the Guidelines for the Care and Use of Laboratory Animals issued by the National Institute of Infectious Diseases. The protocol was approved by the ethics committee of the National Institute of Infectious Diseases.