TAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response

Jianwen Chen; Ruirui He; Wanwei Sun; Ru Gao; Qianwen Peng; Liwen Zhu; Yanyun Du; Xiaojian Ma; Xiaoli Guo; Huazhi Zhang; Chengcheng Tan; Junhan Wang; Wei Zhang; Xiufang Weng; Jianghong Man; Hermann Bauer; Qing K Wang; Bradley N Martin; Cun-Jin Zhang; Xiaoxia Li; Chenhui Wang

doi:10.1038/s41467-020-15564-7

TAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response

Nat Commun. 2020 Apr 20;11(1):1913. doi: 10.1038/s41467-020-15564-7.

Authors

Jianwen Chen^#¹, Ruirui He^#¹, Wanwei Sun², Ru Gao¹, Qianwen Peng¹, Liwen Zhu³, Yanyun Du¹, Xiaojian Ma¹, Xiaoli Guo¹, Huazhi Zhang¹, Chengcheng Tan¹, Junhan Wang⁴, Wei Zhang⁵, Xiufang Weng⁶, Jianghong Man⁷, Hermann Bauer⁸, Qing K Wang^{1

9

10}, Bradley N Martin¹¹, Cun-Jin Zhang¹², Xiaoxia Li¹³, Chenhui Wang^{14

15}

Affiliations

¹ Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
² Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China. [email protected].
³ Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, 210008, China.
⁴ University-Affiliated Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China.
⁵ Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁶ Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
⁷ State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, 100850, China.
⁸ Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195, Berlin, Germany.
⁹ Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
¹⁰ Department of Molecular Medicine, Department of Genetics and Genome Science, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
¹¹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹² Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, 210008, China. [email protected].
¹³ Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, 44106, USA.
¹⁴ Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China. [email protected].
¹⁵ Wuhan Institute of Biotechnology, Wuhan, Hubei, 430070, China. [email protected].

^# Contributed equally.

Abstract

The TAGAP gene locus has been linked to several infectious diseases or autoimmune diseases, including candidemia and multiple sclerosis. While previous studies have described a role of TAGAP in T cells, much less is known about its function in other cell types. Here we report that TAGAP is required for Dectin-induced anti-fungal signaling and proinflammatory cytokine production in myeloid cells. Following stimulation with Dectin ligands, TAGAP is phosphorylated by EPHB2 at tyrosine 310, which bridges proximal Dectin-induced EPHB2 activity to downstream CARD9-mediated signaling pathways. During Candida albicans infection, mice lacking TAGAP mount defective immune responses, impaired Th17 cell differentiation, and higher fungal burden. Similarly, in experimental autoimmune encephalomyelitis model of multiple sclerosis, TAGAP deficient mice develop significantly attenuated disease. In summary, we report that TAGAP plays an important role in linking Dectin-induced signaling to the promotion of effective T helper cell immune responses, during both anti-fungal host defense and autoimmunity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antifungal Agents / immunology*
Antifungal Agents / pharmacology
CARD Signaling Adaptor Proteins / metabolism
Candidiasis / immunology*
Cell Differentiation*
Cytokines / metabolism
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / microbiology
Female
GTPase-Activating Proteins / chemistry*
GTPase-Activating Proteins / genetics
GTPase-Activating Proteins / metabolism*
Humans
Lectins, C-Type / metabolism
Male
Mice, Knockout
Multiple Sclerosis / complications
Multiple Sclerosis / immunology
Phosphorylation
Receptor, EphB2 / immunology
Receptor, EphB2 / metabolism*
Receptors, Immunologic
Receptors, Pattern Recognition / metabolism
Signal Transduction / drug effects*
Th17 Cells / immunology
Th17 Cells / metabolism*

Substances

Antifungal Agents
CARD Signaling Adaptor Proteins
Card9 protein, mouse
Clec4d protein, mouse
Cytokines
GTPase-Activating Proteins
Lectins, C-Type
Receptors, Immunologic
Receptors, Pattern Recognition
TAGAP protein, mouse
dectin 1
dectin-2, mouse
Ephb2 protein, mouse
Receptor, EphB2