Journal
IMMUNITY
Volume 45, Issue 2, Pages 319-332Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2016.07.015
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Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Science and Technology Agency
- Eisai Co., Ltd.
- MEXT/Japan Society for the Promotion of Science (KAKENHI) [24390246, 24118002, 25860368]
- Grant for Strategic Research Promotion from Yokohama City University
- Fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program
- Grants-in-Aid for Scientific Research [15K19028, 25860368, 24118002, 16K19161, 15H05787, 16H05230, 24390246, 16H07105] Funding Source: KAKEN
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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.
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