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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity*
  • Cells, Cultured
  • Cytokines / metabolism
  • Dendritic Cells / immunology*
  • Humans
  • Immune Tolerance
  • Immunity, Innate
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism*
  • Lupus Erythematosus, Systemic / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein Binding
  • Signal Transduction
  • Toll-Like Receptors / metabolism
  • Transcriptional Activation
  • Ubiquitination
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism*


  • Cytokines
  • Interferon Regulatory Factors
  • Irf5 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Toll-Like Receptors
  • lyn protein-tyrosine kinase
  • src-Family Kinases