Human T cell lymphotropic virus 1 manipulates interferon regulatory signals by controlling the TAK1-IRF3 and IRF4 pathways.
We previously reported that human T cell lymphotropic virus 1 (HTLV-1) Tax oncoprotein constitutively activates transforming growth factor-beta-activated kinase 1 (TAK1). Here, we established Tax-positive HuT-102 cells stably transfected with a short hairpin RNA vector (HuT-shTAK1 cells) and investigated the physiological function of TAK1. Microarray analysis demonstrated that several interferon (IFN)-inducible genes, including chemokines such as CXCL10 and CCL5, were significantly down-regulated in HuT-shTAK1 cells. In contrast, Tax-mediated constitutive activation of nuclear factor-kappaB (NF-kappaB) was intact in HuT-shTAK1 cells. IFN-regulatory factor 3 (IRF3), a critical transcription factor in innate immunity to viral infection, was constitutively activated in a Tax-dependent manner. Activation of IRF3 and IRF3-dependent gene expressions was dependent on TAK1 and TANK-binding kinase 1 (TBK1). On the other hand, IRF4, another member in the IRF family of transcription factors overexpressed in a Tax-independent manner, negatively regulated TAK1-dependent IRF3 transcriptional activity. Together, HTLV-1 manipulates IFN signaling by regulating both positive and negative IRFs.
Suzuki
Shunsuke
S
Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.
Zhou
Yue
Y
Refaat
Alaa
A
Takasaki
Ichiro
I
Koizumi
Keiichi
K
Yamaoka
Shoji
S
Tabuchi
Yoshiaki
Y
Saiki
Ikuo
I
Sakurai
Hiroaki
H
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D018946:Chemokine CCL5 / Q000235:genetics; D054357:Chemokine CXCL10 / Q000235:genetics; D015683:Gene Products, gag / Q000235:genetics; D016356:Gene Products, tax / Q000235:genetics / Q000502:physiology; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D007372:Interferons / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000099218:Interferon Regulatory Factor-4; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D015683:Gene Products, gag; D016356:Gene Products, tax; D050838:Interferon Regulatory Factor-3; D050835:Interferon Regulatory Factors; D007372:Interferons; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D000099218:Interferon Regulatory Factor-4; D000099151:MAP Kinase Kinase Kinase 7; C114753:CXCL10 protein, human; C484290:IFIT1 protein, human; C494232:IRF3 protein, human