TRAF6 establishes innate immune responses by activating NF-kappaB and IRF7 upon sensing cytosolic viral RNA and DNA.
BACKGROUND
In response to viral infection, the innate immune system recognizes viral nucleic acids and then induces production of proinflammatory cytokines and type I interferons (IFNs). Toll-like receptor 7 (TLR7) and TLR9 detect viral RNA and DNA, respectively, in endosomal compartments, leading to the activation of nuclear factor kappaB (NF-kappaB) and IFN regulatory factors (IRFs) in plasmacytoid dendritic cells. During such TLR signaling, TNF receptor-associated factor 6 (TRAF6) is essential for the activation of NF-kappaB and the production of type I IFN. In contrast, RIG-like helicases (RLHs), cytosolic RNA sensors, are indispensable for antiviral responses in conventional dendritic cells, macrophages, and fibroblasts. However, the contribution of TRAF6 to the detection of cytosolic viral nucleic acids has been controversial, and the involvement of TRAF6 in IRF activation has not been adequately addressed.


RESULTS
Here we first show that TRAF6 plays a critical role in RLH signaling. The absence of TRAF6 resulted in enhanced viral replication and a significant reduction in the production of IL-6 and type I IFNs after infection with RNA virus. Activation of NF-kappaB and IRF7, but not that of IRF3, was significantly impaired during RLH signaling in the absence of TRAF6. TGFbeta-activated kinase 1 (TAK1) and MEKK3, whose activation by TRAF6 during TLR signaling is involved in NF-kappaB activation, were not essential for RLH-mediated NF-kappaB activation. We also demonstrate that TRAF6-deficiency impaired cytosolic DNA-induced antiviral responses, and this impairment was due to defective activation of NF-kappaB and IRF7.


CONCLUSIONS
Thus, TRAF6 mediates antiviral responses triggered by cytosolic viral DNA and RNA in a way that differs from that associated with TLR signaling. Given its essential role in signaling by various receptors involved in the acquired immune system, TRAF6 represents a key molecule in innate and antigen-specific immune responses against viral infection.
Konno
Hiroyasu
H
Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Yamamoto
Takuya
T
Yamazaki
Kohsuke
K
Gohda
Jin
J
Akiyama
Taishin
T
Semba
Kentaro
K
Goto
Hideo
H
Kato
Atsushi
A
Yujiri
Toshiaki
T
Imai
Takahiko
T
Kawaguchi
Yasushi
Y
Su
Bing
B
Takeuchi
Osamu
O
Akira
Shizuo
S
Tsunetsugu-Yokota
Yasuko
Y
Inoue
Jun-ichiro
J
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003600:Cytosol / Q000201:enzymology / Q000276:immunology / Q000821:virology*; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004279:DNA, Viral / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism*; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012328:RNA Viruses / Q000302:isolation & purification; D012367:RNA, Viral / Q000276:immunology*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D053487:DEAD-box RNA Helicases; D004279:DNA, Viral; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D012367:RNA, Viral; D048029:TNF Receptor-Associated Factor 6; D000099151:MAP Kinase Kinase Kinase 7; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; C100814:Tank protein, mouse; C498588:Tbk1 protein, mouse; C482626:Map3k3 protein, mouse