title: Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF-kappaB.
abstract: Adult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). The activation of NF-kappaB by Tax has been reported to play a crucial role in HTLV-1-induced transformation. The HTLV-1 bZIP factor (HBZ), which is encoded by an mRNA of the opposite polarity of the viral genomic RNA, is involved in both T cell proliferation and suppression of Tax-mediated viral gene transcription, suggesting that HBZ cooperates closely with Tax. In the present study, we observed that HBZ specifically suppressed NF-kappaB-driven transcription mediated by p65 (the classical pathway) without inhibiting the alternative NF-kappaB signaling pathway. In an immunoprecipitation assay, HBZ bound to p65 and diminished the DNA binding capacity of p65. In addition, HBZ induced p65 degradation through increasing the expression of the PDLIM2 gene, which encodes a ubiquitin E3 ligase for p65. Finally, HBZ actually repressed the transcription of some classical NF-kappaB target genes, such as IL-8, IL2RA, IRF4, VCAM-1, and VEGF. Selective suppression of the classical NF-kappaB pathway by HBZ renders the alternative NF-kappaB pathway predominant after activation of NF-kappaB by Tax or other stimuli, which might be critical for oncogenesis.
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Tiejun
authors.initials: T
authors.lastname: Zhao
authors.forename: Jun-ichirou
authors.initials: J
authors.lastname: Yasunaga
authors.forename: Yorifumi
authors.initials: Y
authors.lastname: Satou
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakao
authors.forename: Masahiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujii
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000502:physiology*; D002460:Cell Line; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D016356:Gene Products, tax / Q000502:physiology; D017930:Genes, Reporter; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D060588:LIM Domain Proteins; D008840:Microfilament Proteins / Q000096:biosynthesis / Q000235:genetics; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012191:Retroviridae Proteins; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D054875:Ubiquitination; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D014764:Viral Proteins / Q000502:physiology*; D000099218:Interferon Regulatory Factor-4
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D016356:Gene Products, tax; D020672:I-kappa B Proteins; D050835:Interferon Regulatory Factors; D053645:Interleukin-2 Receptor alpha Subunit; D016209:Interleukin-8; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D012191:Retroviridae Proteins; D051996:Transcription Factor RelA; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D014764:Viral Proteins; D000099218:Interferon Regulatory Factor-4; C479751:HBZ protein, human T-cell leukemia virus type I; C508017:IL2RA protein, human; C000606204:NFKBIA protein, human; C502929:PDLIM2 protein, human; C498143:RELA protein, human; C467484:VEGFA protein, human; C514970:tax protein, Human T-lymphotrophic virus 1