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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
Immunity (Cambridge, Mass.), 08/2016, Volume: 45, Issue: 2Journal Article
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.
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