CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretion
Open Access
- 27 March 2006
- journal article
- Published by Rockefeller University Press in The Journal of cell biology
- Vol. 172 (7), 1057-1068
- https://doi.org/10.1083/jcb.200508058
Abstract
Toll-like receptors (TLRs) recognize molecular patterns preferentially expressed by pathogens. In endosomes, TLR9 is activated by unmethylated bacterial DNA, resulting in proinflammatory cytokine secretion via the adaptor protein MyD88. We demonstrate that CpG oligonucleotides activate a TLR9-independent pathway initiated by two Src family kinases, Hck and Lyn, which trigger a tyrosine phosphorylation–mediated signaling cascade. This cascade induces actin cytoskeleton reorganization, resulting in cell spreading, adhesion, and motility. CpG-induced actin polymerization originates at the plasma membrane, rather than in endosomes. Chloroquine, an inhibitor of CpG-triggered cytokine secretion, blocked TLR9/MyD88-dependent cytokine secretion as expected but failed to inhibit CpG-induced Src family kinase activation and its dependent cellular responses. Knock down of Src family kinase expression or the use of specific kinase inhibitors blocked MyD88-dependent signaling and cytokine secretion, providing evidence that tyrosine phosphorylation is both CpG induced and an upstream requirement for the engagement of TLR9. The Src family pathway intersects the TLR9–MyD88 pathway by promoting the tyrosine phosphorylation of TLR9 and the recruitment of Syk to this receptor.Keywords
This publication has 60 references indexed in Scilit:
- Focal adhesion kinase: in command and control of cell motilityNature Reviews Molecular Cell Biology, 2005
- Talin: an emerging focal point of adhesion dynamicsCurrent Opinion in Cell Biology, 2004
- TLR9 signals after translocating from the ER to CpG DNA in the lysosomeNature Immunology, 2004
- Expression and tyrosine phosphorylation of Cbl regulates macrophage chemokinetic and chemotactic movementJournal of Cellular Physiology, 2003
- CD1-dependent dendritic cell instructionNature Immunology, 2002
- Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartmentsEuropean Journal of Immunology, 2002
- p59Hck Isoform Induces F-actin Reorganization to Form Protrusions of the Plasma Membrane in a Cdc42- and Rac-dependent MannerPublished by Elsevier BV ,2002
- Combating malaria in AfricaTrends in Parasitology, 2002
- A role for Toll in autoimmunityNature Immunology, 2002
- An in vitro bioassay for quantitation of human interferons by measurements of antiproliferative activity on a continuous human lymphoma cell lineBiologicals, 1990