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

被引：82

作者：

Ban, Tatsuma ^{[1
]}

Sato, Go R. ^{[1
]}

Nishiyama, Akira ^{[1
]}

Akiyama, Ai ^{[1
]}

Takasuna, Marie ^{[1
]}

Umehara, Marina ^{[1
]}

Suzuki, Shinsuke ^{[1
,2
]}

Ichino, Motohide ^{[1
]}

Matsunaga, Satoko ^{[3
]}

Kimura, Ayuko ^{[4
]}

Kimura, Yayoi ^{[4
]}

Yanai, Hideyuki ^{[5
]}

Miyashita, Sadakazu ^{[6
]}

Kuromitsu, Junro ^{[6
]}

Tsukahara, Kappei ^{[6
]}

Yoshimatsu, Kentaro ^{[6
]}

Endo, Itaru ^{[2
]}

Yamamoto, Tadashi ^{[7
]}

Hirano, Hisashi ^{[4
]}

Ryo, Akihide ^{[3
]}

Taniguchi, Tadatsugu ^{[5
]}

Tamura, Tomohiko ^{[1
]}

机构：

[1] Yokohama City Univ, Grad Sch Med, Dept Immunol, Yokohama, Kanagawa 2360004, Japan

[2] Yokohama City Univ, Grad Sch Med, Dept Gastroenterol Surg, Yokohama, Kanagawa 2360004, Japan

[3] Yokohama City Univ, Grad Sch Med, Dept Microbiol, Yokohama, Kanagawa 2360004, Japan

[4] Yokohama City Univ, Adv Med Res Ctr, Yokohama, Kanagawa 2360004, Japan

[5] Univ Tokyo, Inst Ind Sci, Dept Mol Immunol, Tokyo 1538505, Japan

[6] Eisai & Co Ltd, Tsukuba Res Labs, Ibaraki 3002635, Japan

[7] Grad Univ, Okinawa Inst Sci & Technol, Cell Signal Unit, Okinawa 9040495, Japan

来源：

IMMUNITY | 2016年 / 45卷 / 02期

基金：

日本学术振兴会; 日本科学技术振兴机构;

关键词：

INTERFERON REGULATORY FACTOR; SYSTEMIC-LUPUS-ERYTHEMATOSUS; TOLL-LIKE RECEPTORS; DENDRITIC CELLS; B-CELLS; I INTERFERON; IRF5(-/-) MICE; DISEASE; PATHOGENESIS; EXPRESSION;

D O I：

10.1016/j.immuni.2016.07.015

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：319 / 332

页数：14

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