title: HTLV-1 HBZ positively regulates the mTOR signaling pathway via inhibition of GADD34 activity in the cytoplasm.
abstract: Human T-cell leukemia virus type-1 (HTLV-1) infection causes adult T-cell leukemia (ATL). Modulation of the transcriptional control of cellular genes by HTLV-1 is thought to be associated with the development of ATL. The viral protein HTLV-1 basic leucine-zipper factor (HBZ) has been shown to dysregulate the activity of cellular transcription factors. Here, we demonstrate that HBZ is exported from the nucleus to the cytoplasm, where it activates the mammalian target of rapamycin (mTOR) signaling pathway through an association with growth arrest and DNA damage gene 34 (GADD34). The N-terminal region of HBZ interacts with the C-terminal region of GADD34. HBZ contains a functional nuclear export signal (NES) sequence within its N-terminal region and it is exported from the nucleus via the CRM1-dependent pathway. Nuclear export of HBZ is essential for its interaction with GADD34 and increased phosphorylation of S6 kinase, which is an established downstream target of the mTOR pathway. Starvation-induced autophagy is significantly suppressed by the overexpression of HBZ. These findings indicate that HBZ is actively exported to the cytoplasm, where it dysregulates the function of cellular factors.
authors.affiliation: Faculty of Engineering, Tokushima Bunri University, Sanuki, Kagawa, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Mukai
authors.affiliation: 1] Faculty of Engineering, Tokushima Bunri University, Sanuki, Kagawa, Japan [2] Faculty of Pharmaceutical Science at Kagawa Campus, Tokushima Bunri University, Sanuki, Kagawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ohshima
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D057809:HEK293 Cells; D015368:Human T-lymphotropic virus 1; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D049790:Nuclear Export Signals; D054645:Protein Phosphatase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012191:Retroviridae Proteins; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014162:Transfection; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000097606:Exportin 1 Protein
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D028884:Karyopherins; D049790:Nuclear Export Signals; D054645:Protein Phosphatase 1; D018160:Receptors, Cytoplasmic and Nuclear; D012191:Retroviridae Proteins; D058570:TOR Serine-Threonine Kinases; D014764:Viral Proteins; D000097606:Exportin 1 Protein; C479751:HBZ protein, human T-cell leukemia virus type I; C087519:PPP1R15A protein, human