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Tyrosine phosphatase SHP-2 mediates C-type lectin receptor–induced activation of the kinase Syk and anti-fungal TH17 responses

Nature Immunology volume 16, pages 642652 (2015) | Download Citation

Abstract

Fungal infection stimulates the canonical C-type lectin receptor (CLR) signaling pathway via activation of the tyrosine kinase Syk. Here we identify a crucial role for the tyrosine phosphatase SHP-2 in mediating CLR-induced activation of Syk. Ablation of the gene encoding SHP-2 (Ptpn11; called 'Shp-2' here) in dendritic cells (DCs) and macrophages impaired Syk-mediated signaling and abrogated the expression of genes encoding pro-inflammatory molecules following fungal stimulation. Mechanistically, SHP-2 operated as a scaffold, facilitating the recruitment of Syk to the CLR dectin-1 or the adaptor FcRγ, through its N-SH2 domain and a previously unrecognized carboxy-terminal immunoreceptor tyrosine-based activation motif (ITAM). We found that DC-derived SHP-2 was crucial for the induction of interleukin 1β (IL-1β), IL-6 and IL-23 and anti-fungal responses of the TH17 subset of helper T cells in controlling infection with Candida albicans. Together our data reveal a mechanism by which SHP-2 mediates the activation of Syk in response to fungal infection.

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Acknowledgements

We thank J.V. Ravetch (The Rockefeller University) for FcRγ-deficient mice; Y. Iwakura (The University of Tokyo) for dectin-1-deficient mice; S. Yamasaki (Kyushu University) for Mincle-deficient mice; B. Qian for technical assistance in histology; and Y. Xu and J. Yan for technical assistance in confocal microscopy. Support by National Science and Technology Major Projects (2014CB541902 to H.X.; and 81270627 to H.H.Z.), the National Natural Science Foundation of China (31070779 and 31170862 to H.X.; 31270917 to M.D.; and 31100623 to A.Z.), the US National Institutes of Health (R01HL096125 to G.-S.F.; P01 HL103453 to X.Li; and R01EY018612 to E.P.), the Chinese Academy of Sciences “100-talent” program (H.X.), the National Program for Returned Overseas Talents (H.X.) and the Science and Technology Commission of Shanghai Municipality (Pujiang program 12PJ1406100 for H.H.Z.).

Author information

Affiliations

  1. Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.

    • Zihou Deng
    • , Shixin Ma
    • , Aiping Zang
    • , Yiyuan Fang
    • , Tiantian Li
    • , Huanjing Shi
    • , Mei Liu
    • , Min Du
    • , Guangxun Meng
    • , Changbin Chen
    • , Yan Zhang
    • , Xiaoming Zhang
    •  & Hui Xiao
  2. Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Hao Zhou
    •  & Xiaoxia Li
  3. Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Ohio, USA.

    • Patricia R Taylor
    •  & Eric Pearlman
  4. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

    • Helen He Zhu
  5. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

    • Jiangye Chen
  6. Shanghai Institute of Immunology and Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

    • Fubin Li
  7. Department of Immunology, Tongji University School of Medicine, Shanghai, China.

    • Xin-Ming Jia
  8. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Xin Lin
  9. Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.

    • Gen-Sheng Feng

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Contributions

Z.D. and H.X. designed the research; Z.D., S.M., H.Z., A.Z., Y.F., T.L., H.S., M.L. and M.D. performed experiments; P.R.T., H.H.Z., J.C., G.M., F.L., C.C., Y.Z., X.-M.J., X. Lin, X.Z., E.P., X.Li and G.-S.F. provided materials and technical support; Z.D., H.Z., X.Li and H.X. analyzed the data; and Z.D., E.P., X.Li, G.-S.F. and H.X. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Hui Xiao.

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https://doi.org/10.1038/ni.3155

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