title: HTLV-1 Tax deregulates autophagy by recruiting autophagic molecules into lipid raft microdomains.
abstract: The retroviral oncoprotein Tax from human T-cell leukemia virus type 1 (HTLV-1), an etiological factor that causes adult T-cell leukemia and lymphoma, has a crucial role in initiating T-lymphocyte transformation by inducing oncogenic signaling activation. We here report that Tax is a determining factor for dysregulation of autophagy in HTLV-1-transformed T cells and Tax-immortalized CD4 memory T cells. Tax facilitated autophagic process by activating inhibitor of κB (IκB) kinase (IKK) complex, which subsequently recruited an autophagy molecular complex containing Beclin1 and Bif-1 to the lipid raft microdomains. Tax engaged a crosstalk between IKK complex and autophagic molecule complex by directly interacting with both complexes, promoting assembly of LC3+ autophagosomes. Moreover, expression of lipid raft-targeted Bif-1 or Beclin1 was sufficient to induce formation of LC3+ autophagosomes, suggesting that Tax recruitment of autophagic molecules to lipid rafts is a dominant strategy to deregulate autophagy in the context of HTLV-1 transformation of T cells. Furthermore, depletion of autophagy molecules such as Beclin1 and PI3 kinase class III resulted in impaired growth of HTLV-1-transformed T cells, indicating a critical role of Tax-deregulated autophagy in promoting survival and transformation of virally infected T cells.
authors.affiliation: 1] Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA [2] Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ren
authors.affiliation: Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA.
authors.forename: T P
authors.initials: TP
authors.lastname: Loughran
authors.affiliation: Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: S-C
authors.initials: SC
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, USA.
authors.forename: H-G
authors.initials: HG
authors.lastname: Wang
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Cheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D019169:Jurkat Cells; D021962:Membrane Microdomains / Q000378:metabolism* / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010588:Phagosomes / Q000378:metabolism / Q000821:virology; D019869:Phosphatidylinositol 3-Kinases; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D016356:Gene Products, tax; C502070:MAP1LC3B protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C429293:SH3GLB1 protein, human; D049452:Green Fluorescent Proteins; D019869:Phosphatidylinositol 3-Kinases; D051550:I-kappa B Kinase