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Toll-like receptor 2–mediated NF-κB activation requires a Rac1-dependent pathway

Nature Immunology volume 1, pages 533–540 (2000)Cite this article

Abstract

Mammalian Toll-like receptors (TLRs) are expressed on innate immune cells and respond to the membrane components of Gram-positive or Gram-negative bacteria. When activated, they convey signals to transcription factors that orchestrate the inflammatory response. However, the intracellular signaling events following TLR activation are largely unknown. Here we show that TLR2 stimulation by Staphylococcus aureus induces a fast and transient activation of the Rho GTPases Rac1 and Cdc42 in the human monocytic cell line THP-1 and in 293 cells expressing TLR2. Dominant-negative Rac1N17, but not dominant-negative Cdc42N17, block nuclear factor-κB (NF-κB) transactivation. S. aureus stimulation causes the recruitment of active Rac1 and phosphatidylinositol-3 kinase (PI3K) to the TLR2 cytosolic domain. Tyrosine phosphorylation of TLR2 is required for assembly of a multiprotein complex that is necessary for subsequent NF-κB transcriptional activity. A signaling cascade composed of Rac1, PI3K and Akt targets nuclear p65 transactivation independently of IκBα degradation. Thus Rac1 controls a second, IκB–independent, pathway to NF-κB activation and is essential in innate immune cell signaling via TLR2.

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Figure 1: HKSA activates Rac1 and Cdc42 transiently.
Figure 2: Rac1 controls NF-κB activation after TLR2 stimulation.
Figure 3: TLR2 cytosolic domain is associated with active Rac1.
Figure 4: PI3K is recruited by TLR2 and acts downstream of Rac1 in NF-κB activation.
Figure 5: TLR2 and PI3K form a signaling complex that is dependent on TLR2 tyrosine residues.
Figure 6: Rac1 regulates Akt activation by HKSA and subsequent NF-κB activation.
Figure 7: The Rac1 pathway regulates p65 transactivation independently of IκBα degradation.
Figure 8: Proposed model for Toll signaling to NF-κB.

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Acknowledgements

We thank P. Rutledge for excellent secretarial support. Supported by NIH grants GM 37696 (to U. G. K. and to R. J. U.), GM 28485 and AI 15136 (to R. J. U.), HL48872 (to N.M.). N. T. is the recipient of a Boehringer Ingelheim Fonds fellowship.

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  1. Jean-Paul Mira

    Present address: Medical Intensive Care Unit, Cochin University Hospital, 75014, Paris, France

  2. Laurence Arbibe and Jean-Paul Mira: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, The Scripps Research Institute, La Jolla, 92037, CA, USA

    Laurence Arbibe, Jean-Paul Mira, Nicole Teusch, Lois Kline, Mausumee Guha, Nigel Mackman, Richard J. Ulevitch & Ulla G. Knaus

  2. Department of Molecular Biology, Genentech, South San Francisco, 94080-4990, CA, USA

    Paul J. Godowski

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Correspondence to Richard J. Ulevitch.

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Arbibe, L., Mira, JP., Teusch, N. et al. Toll-like receptor 2–mediated NF-κB activation requires a Rac1-dependent pathway. Nat Immunol 1, 533–540 (2000). https://doi.org/10.1038/82797

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