Spatiotemporal mobilization of Toll/IL-1 receptor domain-containing adaptor molecule-1 in response to dsRNA.
TLR3 recognizes viral dsRNA and induces antiviral immune responses. TLR3-mediated cell activation relies on Toll/IL-1R (TIR) domain-containing adaptor molecule-1 (TICAM-1, also named TIR domain-containing adaptor inducing IFN-beta or TRIF), which recruits downstream signaling molecules to activate the transcription factors IFN regulatory factor 3 (IRF-3) and NF-kappaB. The mechanisms by which TICAM-1 is activated and transmits signals remain largely unknown. In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. The receptor-interacting protein 1 (RIP1), a crucial signaling molecule for TICAM-1-mediated NF-kappaB activation, accumulated in the TICAM-1 speckles. In addition, NF-kappaB-activating kinase-associated protein 1 (NAP1), a downstream molecule linking TICAM-1 and the IRF-3-activating kinase TBK1 (TANK-binding kinase 1), was also recruited to the TICAM-1 speckles. Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. Thus, the spatiotemporal mobilization of TICAM-1 in response to dsRNA and the formation of the TICAM-1 speckles containing RIP1 and NAP1 are important for the activation of the TLR3-TICAM-1 pathway.
Funami
Kenji
K
Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan.
Sasai
Miwa
M
Ohba
Yusuke
Y
Oshiumi
Hiroyuki
H
Seya
Tsukasa
T
Matsumoto
Misako
M
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000276:immunology / Q000378:metabolism; D046912:Multiprotein Complexes / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D011506:Proteins / Q000276:immunology / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000276:immunology* / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000276:immunology* / Q000378:metabolism; D012359:tRNA Methyltransferases
C119724:AGFG1 protein, human; D033942:Adaptor Proteins, Vesicular Transport; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D046912:Multiprotein Complexes; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D011506:Proteins; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; C498548:TRMO protein, human; D012359:tRNA Methyltransferases; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human