Selective control of type I IFN induction by the Rac activator DOCK2 during TLR-mediated plasmacytoid dendritic cell activation.
Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity, but also contribute to the pathogenesis of certain autoimmune diseases, by producing large amounts of type I IFNs. Although activation of pDCs is triggered by engagement of nucleotide-sensing toll-like receptors (TLR) 7 and 9, type I IFN induction additionally requires IkappaB kinase (IKK) alpha-dependent activation of IFN regulatory factor (IRF) 7. However, the signaling pathway mediating IKK-alpha activation is poorly defined. We show that DOCK2, an atypical Rac activator, is essential for TLR7- and TLR9-mediated IFN-alpha induction in pDCs. We found that the exposure of pDCs to nucleic acid ligands induces Rac activation through a TLR-independent and DOCK2-dependent mechanism. Although this Rac activation was dispensable for induction of inflammatory cytokines, phosphorylation of IKK-alpha and nuclear translocation of IRF-7 were impaired in Dock2-deficient pDCs, resulting in selective loss of IFN-alpha induction. Similar results were obtained when a dominant-negative Rac mutant was expressed in wild-type pDCs. Thus, the DOCK2-Rac signaling pathway acts in parallel with TLR engagement to control IKK-alpha activation for type I IFN induction. Owing to its hematopoietic cell-specific expression, DOCK2 may serve as a therapeutic target for type I IFN-related autoimmune diseases.
Gotoh
Kazuhito
K
Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Tanaka
Yoshihiko
Y
Nishikimi
Akihiko
A
Nakamura
Risa
R
Yamada
Hisakata
H
Maeda
Naoyoshi
N
Ishikawa
Takahiro
T
Hoshino
Katsuaki
K
Uruno
Takehito
T
Cao
Qinhong
Q
Higashi
Sadayuki
S
Kawaguchi
Yasushi
Y
Enjoji
Munechika
M
Takayanagi
Ryoichi
R
Kaisho
Tsuneyasu
T
Yoshikai
Yasunobu
Y
Fukui
Yoshinori
Y
D000199:Actins / Q000378:metabolism; D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D018258:Herpesvirus 2, Human / Q000276:immunology; D051550:I-kappa B Kinase / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D009980:Influenza A virus / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis* / Q000378:metabolism; D016898:Interferon-alpha / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D016899:Interferon-beta / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000097:blood / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000819:agonists; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
D000199:Actins; C408982:CPG-oligonucleotide; C471356:DOCK2 protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D007093:Imidazoles; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D016898:Interferon-alpha; D053762:Interleukin-12 Subunit p40; C494235:Irf7 protein, mouse; D008562:Membrane Glycoproteins; D009479:Neuropeptides; D009838:Oligodeoxyribonucleotides; C484602:Rac1 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D016899:Interferon-beta; D053592:Interleukin-1 Receptor-Associated Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D020928:Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; C402365:resiquimod