Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Immunity (Cambridge, Mass.), 2016-08, Vol.45 (2), p.319-332

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• 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.