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  • The EMBO Journal (2006) 25, 3335 - 3346
  • doi:10.1038/sj.emboj.7601222

Published online: 6 July 2006

Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling

Ingvild Bjellmo Johnsen1, Thuy Thanh Nguyen1, Monika Ringdal1, Anne Merete Tryggestad1, Oddmund Bakke2, Egil Lien3, Terje Espevik4 and Marit W Anthonsen1

  1. Department of Laboratory Medicine, Children's and Women's Health, Institute of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway
  2. Department of Molecular Biosciences, University of Oslo, Oslo, Norway
  3. Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA
  4. Department of Cancer Research and Molecular Medicine, Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

Correspondence to:

Marit W Anthonsen, Faculty of Medicine, Norwegian University of Science and Technology, MTFS, Olav Kyrresgt. 3, 7489 Trondheim, Norway. Tel.: +47 7257 3351; Fax: +47 7359 8861; E-mails: E-mail: Marit.W.Anthonsen@ntnu.no or ingvild.Johnsen@ntnu.no

Received 25 November 2004; Accepted 13 June 2006

Double-stranded RNA (dsRNA) is produced during the replication cycle of most viruses and triggers antiviral immune responses through Toll-like receptor 3 (TLR3). However, the molecular mechanisms and subcellular compartments associated with dsRNA-TLR3-mediated signaling are largely unknown. Here we show that c-Src tyrosine kinase is activated by dsRNA in human monocyte-derived dendritic cells, and is recruited to TLR3 in a dsRNA-dependent manner. DsRNA-induced activation of interferon-regulatory factor 3 and signal transducer and activator of transcription 1 was abolished in Src kinase-deficient cells, and restored by adding back c-Src, suggesting a central role of c-Src in antiviral immunity. We also provide evidence that TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA, and colocalizes with c-Src on endosomes containing dsRNA in the lumen. These results provide novel insight into the molecular mechanisms of TLR3-mediated signaling, which may contribute to the understanding of innate immune responses during viral infections.

  • Keywords:

    • dendritic cells,
    • signal transduction,
    • Src tyrosine kinase,
    • Toll-like receptor 3