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Immunity. 2016 Aug 16;45(2):319-32. doi: 10.1016/j.immuni.2016.07.015. Epub 2016 Aug 9.

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

Author information

1
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
2
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
3
Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
4
Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan.
5
Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Tokyo 153-8505, Japan.
6
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, Japan.
7
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
8
Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan.
9
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address: tamurat@yokohama-cu.ac.jp.

Abstract

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-╬║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.

PMID:
27521268
DOI:
10.1016/j.immuni.2016.07.015
[Indexed for MEDLINE]
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