Tyrosine phosphatase SHP-2 mediates C-type lectin receptor-induced activation of the kinase Syk and anti-fungal TH17 responses.
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.
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Zihou
Z
Deng
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Shixin
S
Ma
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Hao
H
Zhou
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Aiping
A
Zang
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Yiyuan
Y
Fang
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Tiantian
T
Li
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Huanjing
H
Shi
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Mei
M
Liu
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Min
M
Du
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Ohio, USA.
Patricia R
PR
Taylor
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
HH
Zhu
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
J
Chen
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Guangxun
G
Meng
Shanghai Institute of Immunology and Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Fubin
F
Li
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Changbin
C
Chen
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Yan
Y
Zhang
Department of Immunology, Tongji University School of Medicine, Shanghai, China.
Xin-Ming
XM
Jia
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Xin
0000000309563654
X
Lin
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Xiaoming
X
Zhang
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Ohio, USA.
Eric
E
Pearlman
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Xiaoxia
X
Li
Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.
Gen-Sheng
GS
Feng
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Hui
H
Xiao
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D002177:Candidiasis / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000502:physiology*; D004789:Enzyme Activation; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008264:Macrophages / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017455:Receptors, IgE / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D000099181:Dectin-1
D000946:Antigens, Fungal; D016207:Cytokines; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D011505:Protein-Tyrosine Kinases; D017455:Receptors, IgE; D000072377:Syk Kinase; D000099181:Dectin-1; C113583:Clecsf8 protein, mouse; C000606897:Syk protein, mouse