title: Identification of TBK1 and IKKε, the non-canonical IκB kinases, as crucial pro-survival factors in HTLV-1-transformed T lymphocytes.
abstract: Persistent activation of NF-κB is a prerequisite for development of adult T cell leukemia-lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). HTLV-1 genome encodes a viral transforming protein named Tax, which constitutively activates the canonical IκB kinases (IKK), the central regulator of NF-κB signaling. However, the role of the non-canonical IκB kinases, TBK1 and IKKε, in the pathogenesis of HTLV-1-associated leukemia has not been evaluated. We here show that TBK1/IKKε are crucial pro-survival molecules by maintaining persistent activity of Stat3. Consistent with this finding, silencing Stat3 by the specific shRNA or by the chemical inhibitor ruxolitinib results in drastic impediment of leukemia cell growth. We further find that in HTLV-1-transformed T cells expressing Tax, TBK1 co-localizes with the canonical IκB kinases and Tax in the lipid raft microdomains. The wild type Tax, but not the Tax mutant defective in activating the canonical IKK, promotes the lipid raft translocation of TBK1. This phenomenon correlates with Tax activation of both NF-κB and Stat3. Tax does not interact directly with TBK1/IKKε, and it rather engages a molecular crosstalk between the canonical IKKs and TBK1/IKKε. Our data, therefore, demonstrate a key role of TBK1/IKKε in the survival and proliferation of HTLV-1-transformed T cells and implicate a potential therapy targeting TBK1/IKKε and Stat3 in controlling HTLV-1-mediated oncogenesis.
authors.affiliation: School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, PR China; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, PR China.
authors.forename: Shao-Hui
authors.initials: SH
authors.lastname: Cai
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: hcheng@ihv.umaryland.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Cheng
mesh_terms: D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D016356:Gene Products, tax; D015368:Human T-lymphotropic virus 1; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000821:virology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D016356:Gene Products, tax; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase
keywords: HTLV-1 Tax; IKK; NF-κB; Stat3; T lymphocyte transformation; TBK1/IKKε