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

作者：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

来源：Immunity, 2016, 45(2): 319-332.

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-kappa B 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.

• 出版日期2016-8-16