CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretion

Miguel A. Sanjuan, Navin Rao, Kuei Tai A. Lai, Yin Gu, Siquan Sun, Anja Fuchs, Wai Ping Fung-Leung, Marco Colonna, Lars Karlsson

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

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.

Original languageEnglish
Pages (from-to)1057-1068
Number of pages12
JournalJournal of Cell Biology
Volume172
Issue number7
DOIs
StatePublished - Mar 2006

Fingerprint

Dive into the research topics of 'CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretion'. Together they form a unique fingerprint.

Cite this