title: Phosphatase PTPN4 preferentially inhibits TRIF-dependent TLR4 pathway by dephosphorylating TRAM.
abstract: TLR4 recruits TRIF-related adaptor molecule (TRAM, also known as TICAM2) as a sorting adaptor to facilitate the interaction between TLR4 and TRIF and then initiate TRIF-dependent IRF3 activation. However, the mechanisms by which TRAM links downstream molecules are not fully elucidated. In this study, we show that TRAM undergoes tyrosine phosphorylation upon TLR4 activation and that is required for TLR4-induced IRF3 activation. Protein tyrosine phosphatase nonreceptor type 4 (PTPN4), a protein tyrosine phosphatase, inhibits tyrosine phosphorylation and subsequent cytoplasm translocation of TRAM, resulting in the disturbance of TRAM-TRIF interaction. Consequently, PTPN4 specifically inhibits TRIF-dependent IRF3 activation and IFN-β production in TLR4 pathway. Therefore, our results provide new insight into the TLR4 pathway and identify PTPN4 as a specific inhibitor of TRIF-dependent TLR4 pathway. Targeting PTPN4 would be beneficial for the development of new strategy to control TLR4-associated diseases without unwanted side effects.
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China;
authors.forename: Wanwan
authors.initials: W
authors.lastname: Huai
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China;
authors.forename: Hui
authors.initials: H
authors.lastname: Song
authors.affiliation: Pathology Tissue Bank, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China; and.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250062, China.
authors.forename: Bingqing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China;
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China;
authors.forename: Lihui
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China;
authors.forename: Chengjiang
authors.initials: C
authors.lastname: Gao
authors.affiliation: Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250062, China.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China;
authors.forename: Lining
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China; wzhao@sdu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4 / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4; D018123:Receptors, Interleukin; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C476416:Ticam2 protein, mouse