Lyn Kinase Suppresses the Transcriptional Activity of IRF5 in the TLR-MyD88 Pathway to Restrain the Development of Autoimmunity

• Published in: Immunity (Cambridge, Mass.) Mass.), 2016-08, Vol.45 (2), p.319-332
• Main Authors: Ban, Tatsuma, Sato, Go R., Nishiyama, Akira, Akiyama, Ai, Takasuna, Marie, Umehara, Marina, Suzuki, Shinsuke, Ichino, Motohide, Matsunaga, Satoko, Kimura, Ayuko, Kimura, Yayoi, Yanai, Hideyuki, Miyashita, Sadakazu, Kuromitsu, Junro, Tsukahara, Kappei, Yoshimatsu, Kentaro, Endo, Itaru, Yamamoto, Tadashi, Hirano, Hisashi, Ryo, Akihide, Taniguchi, Tadatsugu, Tamura, Tomohiko
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune diseases; Autoimmunity; Cells, Cultured; Cytokines; Cytokines - metabolism; Dendritic Cells - immunology; Disease; Gene expression; Genomes; Humans; Immune Tolerance; Immunity, Innate; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Kinases; Lupus; Lupus Erythematosus, Systemic - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88 - metabolism; NF-kappa B - metabolism; Phosphorylation; Protein Binding; Proteins; Signal Transduction; src-Family Kinases - genetics; src-Family Kinases - metabolism; Statistical analysis; Studies; Toll-Like Receptors - metabolism; Transcriptional Activation; Ubiquitination
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.07.015

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. [Display omitted] •Lyn binds to and inhibits the activity of IRF5 in the TLR-MyD88 pathway•Lyn inhibits post-translational modifications of IRF5 without Lyn’s kinase activity•Lyn deficiency causes IRF5 hyperactivation in DCs•SLE symptoms in Lyn–/– mice are ameliorated by monoallelic deletion of Irf5 How IRF5 activity is negatively regulated remains largely unknown. Tamura and colleagues identify Lyn as an IRF5-binding protein that suppresses the TLR-MyD88-IRF5 pathway. IRF5 is hyperactivated in Lyn-deficient mice suffering from the autoimmune disease SLE, but reducing the abundance of IRF5 ameliorates the disease development.