title: Lyn Kinase Suppresses the Transcriptional Activity of IRF5 in the TLR-MyD88 Pathway to Restrain the Development of Autoimmunity.
abstract: Interferon regulatory factor-5 (IRF5), a transcription factor critical for the induction of innate immune responses, contributes to the pathogenesis of the autoimmune disease systemic lupus erythematosus (SLE) in humans and mice. Lyn, a Src family kinase, is also implicated in human SLE, and Lyn-deficient mice develop an SLE-like disease. Here, we found that Lyn physically interacted with IRF5 to inhibit ubiquitination and phosphorylation of IRF5 in the TLR-MyD88 pathway, thereby suppressing the transcriptional activity of IRF5 in a manner independent of Lyn's kinase activity. Conversely, Lyn did not inhibit NF-κB signaling, another major branch downstream of MyD88. Monoallelic deletion of Irf5 alleviated the hyperproduction of cytokines in TLR-stimulated Lyn(-/-) dendritic cells and the development of SLE-like symptoms in Lyn(-/-) mice. Our results reveal a role for Lyn as a specific suppressor of the TLR-MyD88-IRF5 pathway and illustrate the importance of fine-tuning IRF5 activity for the maintenance of immune homeostasis.
authors: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors: Tatsuma
authors: T
authors: Ban
authors: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors: Go R
authors: GR
authors: Sato
authors: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors: Akira
authors: A
authors: Nishiyama
authors: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors: Ai
authors: A
authors: Akiyama
authors: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors: Marie
authors: M
authors: Takasuna
authors: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors: Marina
authors: M
authors: Umehara
authors: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors: Shinsuke
authors: S
authors: Suzuki
authors: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors: Motohide
authors: M
authors: Ichino
authors: Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors: Satoko
authors: S
authors: Matsunaga
authors: Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan.
authors: Ayuko
authors: A
authors: Kimura
authors: Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan.
authors: Yayoi
authors: Y
authors: Kimura
authors: Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Tokyo 153-8505, Japan.
authors: Hideyuki
authors: H
authors: Yanai
authors: Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, Japan.
authors: Sadakazu
authors: S
authors: Miyashita
authors: Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, Japan.
authors: Junro
authors: J
authors: Kuromitsu
authors: Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, Japan.
authors: Kappei
authors: K
authors: Tsukahara
authors: Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, Japan.
authors: Kentaro
authors: K
authors: Yoshimatsu
authors: Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors: Itaru
authors: I
authors: Endo
authors: Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan.
authors: Tadashi
authors: T
authors: Yamamoto
authors: Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan.
authors: Hisashi
authors: H
authors: Hirano
authors: Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors: Akihide
authors: A
authors: Ryo
authors: Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Tokyo 153-8505, Japan.
authors: Tadatsugu
authors: T
authors: Taniguchi
authors: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address: tamurat@yokohama-cu.ac.jp.
authors: Tomohiko
authors: T
authors: Tamura
mesh_terms: D000818:Animals; D015551:Autoimmunity; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D015533:Transcriptional Activation; D054875:Ubiquitination; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051193:Toll-Like Receptors; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases