title: HTLV-1 bZIP factor enhances TGF-β signaling through p300 coactivator.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is etiologically associated with adult T-cell leukemia. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the provirus, is involved in both regulation of viral gene transcription and T-cell proliferation. We showed in this report that HBZ interacted with Smad2/3, and enhanced transforming growth factor-β (TGF-β)/Smad transcriptional responses in a p300-dependent manner. The N-terminal LXXLL motif of HBZ was responsible for HBZ-mediated TGF-β signaling activation. In a serial immunoprecipitation assay, HBZ, Smad3, and p300 formed a ternary complex, and the association between Smad3 and p300 was markedly enhanced in the presence of HBZ. In addition, HBZ could overcome the repression of the TGF-β response by Tax. Finally, HBZ expression resulted in enhanced transcription of Pdgfb, Sox4, Ctgf, Foxp3, Runx1, and Tsc22d1 genes and suppression of the Id2 gene; such effects were similar to those by TGF-β. In particular, HBZ induced Foxp3 expression in naive T cells through Smad3-dependent TGF-β signaling. Our results suggest that HBZ, by enhancing TGF-β signaling and Foxp3 expression, enables HTLV-1 to convert infected T cells into regulatory T cells, which is thought to be a critical strategy for virus persistence.
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: Yorifumi
authors.initials: Y
authors.lastname: Satou
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugata
authors.forename: Paola
authors.initials: P
authors.lastname: Miyazato
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Green
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D015967:Gene Expression Regulation, Viral; D015490:HTLV-I Infections / Q000150:complications; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary; D012191:Retroviridae Proteins; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D051858:Forkhead Transcription Factors; C479751:HBZ protein, human T-cell leukemia virus type I; D012191:Retroviridae Proteins; D051896:Smad Proteins, Receptor-Regulated; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D014764:Viral Proteins; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human