title: Syk mediates IL-17-induced CCL20 expression by targeting Act1-dependent K63-linked ubiquitination of TRAF6.
abstract: IL-17 has an important role in the immunopathogenesis of autoimmune diseases, and spleen tyrosine kinase (Syk) has been implicated as a critical molecule in the signaling pathways of various immunoreceptors. Chemokine (C-C motif) ligand 20 (CCL20) interacts with chemokine (C-C motif) receptor 6 to recruit IL-17-producing cells into the skin to promote progression of psoriasis. Herein we investigate how Syk regulates IL-17 signaling to affect CCL20 expression in primary human epidermal keratinocytes. We found that IL-17 can induce CCL20 expression and activate TAK, IKK, NF-κB, c-Jun N-terminal kinase, and Syk. Data of TAK inhibitor and Syk small interfering RNA (siRNA) indicate Syk being an upstream molecule of TAK in IL-17-elicited signaling. The promoter activity assay combined with site-directed mutagenesis showed that IL-17-elicited CCL20 upregulation is depending on the Syk-mediated NF-κB pathway. Immunoprecipitation also indicated the interaction of Syk with signal molecules of IL-17R, such as TRAF6 and Act1, under IL-17A stimulation. However, the essential signaling events including TRAF6 interaction with Act1 and TRAF6 polyubiquitination under IL-17A stimulation were diminished by Syk siRNA and pharmacologically inhibiting Syk. Taken together, we identify Syk as an upstream signaling molecule in IL-17A-induced Act1-TRAF6 interaction in keratinocytes, and inhibition of Syk can attenuate CCL20 production, which highlights Syk as a potential therapeutic target for inflammatory skin diseases such as psoriasis.
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City, Taiwan; Department of Dermatology, Mackay Memorial Hospital, Taipei, Taiwan; Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, New Taipei City, Taiwan.
authors.forename: Nan-Lin
authors.initials: NL
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Duen-Yi
authors.initials: DY
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsin-Ni
authors.initials: HN
authors.lastname: Tsou
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ying-Cing
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan. Electronic address: wwllaura1119@ntu.edu.tw.
authors.forename: Wan-Wan
authors.initials: WW
authors.lastname: Lin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000235:genetics*; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D000072377:Syk Kinase; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000502:physiology*; D054875:Ubiquitination; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054418:Chemokine CCL20; D020381:Interleukin-17; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D000072377:Syk Kinase; D048029:TNF Receptor-Associated Factor 6; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D000099151:MAP Kinase Kinase Kinase 7; C108355:CCL20 protein, human; C414202:TRAF3IP2 protein, human; C000606896:SYK protein, human