title: Enhanced Stabilization of MCL1 by the Human T-Cell Leukemia Virus Type 1 bZIP Factor Is Modulated by Blocking the Recruitment of Cullin 1 to the SCF Complex.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is the etiological agent of adult T-cell leukemia (ATL). The HTLV-1 basic leucine zipper factor (HBZ), which is encoded by the minus strand of the provirus, is constitutively expressed in all ATL patient cells and likely contributes to the development and maintenance of ATL. Furthermore, the overexpression of the myeloid cell leukemia 1 (MCL1) protein is frequently observed in hematological cancers as well as several other types of cancers. Here, we found that the expression of HBZ in cells stabilized MCL1 protein expression and suppressed the MCL1-mediated release of cytochrome c from the mitochondria. This effect was mediated by inhibition of the ubiquitin-dependent degradation of MCL1. In a serial binding assay, HBZ interacted with cullin 1 (CUL1) through a head-to-tail interaction. The association between CUL1 and Skp1, which serves as the molecular scaffold for the components of SCF ubiquitin ligase complexes, was markedly repressed in the presence of HBZ. Mechanistic analysis indicated that HBZ abrogated the CUL1 association with Skp1, which in turn promoted the cellular expression of MCL1. This novel function of HBZ likely plays a role in the viral pathogenesis of HTLV-1 and provides important insights into our understanding of the development of ATL.
authors.affiliation: Faculty of Pharmaceutical Science at Kagawa Campus, Tokushima Bunri University, Sanuki, Kagawa, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Mukai
authors.affiliation: Faculty of Pharmaceutical Science at Kagawa Campus, Tokushima Bunri University, Sanuki, Kagawa, Japan ohshimat@kph.bunri-u.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ohshima
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D044842:Cullin Proteins / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D057809:HEK293 Cells; D015490:HTLV-I Infections / Q000378:metabolism*; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry / Q000378:metabolism*; D041681:NIH 3T3 Cells; D055550:Protein Stability; D012191:Retroviridae Proteins / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C100318:Cullin 1; D044842:Cullin Proteins; C479751:HBZ protein, human T-cell leukemia virus type I; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D012191:Retroviridae Proteins; D044786:S-Phase Kinase-Associated Proteins; C097351:SKP1 protein, human; D045304:Cytochromes c; D044843:SKP Cullin F-Box Protein Ligases