title: Suppression of Type I Interferon Production by Human T-Cell Leukemia Virus Type 1 Oncoprotein Tax through Inhibition of IRF3 Phosphorylation.
abstract: Infection with human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and tropical spastic paraparesis. Type I interferons (IFNs) are key effectors of the innate antiviral response, and IFN-α combined with the nucleoside reverse transcriptase inhibitor zidovudine is considered the standard first-line therapy for ATL. HTLV-1 oncoprotein Tax is known to suppress innate IFN production and response but the underlying mechanisms remain to be fully established. In this study, we report on the suppression of type I IFN production by HTLV-1 Tax through interaction with and inhibition of TBK1 kinase that phosphorylates IRF3. Induced transcription of IFN-β was severely impaired in HTLV-1-transformed ATL cells and freshly infected T lymphocytes. The ability to suppress IRF3 activation was ascribed to Tax. The expression of Tax alone sufficiently repressed the induction of IFN production by RIG-I plus PACT, cGAMP synthase plus STING, TBK1, IKKε, IRF3, and IRF7, but not by IRF3-5D, a dominant-active phosphomimetic mutant. This suggests that Tax perturbs IFN production at the step of IRF3 phosphorylation. Tax mutants deficient for CREB or NF-κB activation were fully competent in the suppression of IFN production. Coimmunoprecipitation experiments confirmed the association of Tax with TBK1, IKKε, STING, and IRF3.In vitrokinase assay indicated an inhibitory effect of Tax on TBK1-mediated phosphorylation of IRF3. Taken together, our findings suggested a new mechanism by which HTLV-1 oncoprotein Tax circumvents the production of type I IFNs in infected cells. Our findings have implications in therapeutic intervention of ATL.
  
  
  OBJECTIVE
  Human T-cell leukemia virus type 1 (HTLV-1) is the cause of adult T-cell leukemia (ATL), an aggressive and fatal blood cancer, as well as another chronic disabling disease of the spinal cord. Treatments are unsatisfactory, and options are limited. A combination of antiviral cellular protein alpha interferon and zidovudine, which is an inhibitor of a viral enzyme called reverse transcriptase, has been recommended as the standard first-line therapy for ATL. Exactly how HTLV-1 interacts with the cellular machinery for interferon production and action is not well understood. Our work sheds light on the mechanism of action for the inhibition of interferon production by an HTLV-1 oncogenic protein called Tax. Our findings might help to improve interferon-based anti-HTLV-1 and anti-ATL therapy.
authors.affiliation: Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Chun-Kit
authors.initials: CK
authors.lastname: Yuen
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Chan
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Sin-Yee
authors.initials: SY
authors.lastname: Fung
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Pei-Hui
authors.initials: PH
authors.lastname: Wang
authors.affiliation: Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Wan-Man
authors.initials: WM
authors.lastname: Wong
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Hei-Man Vincent
authors.initials: HV
authors.lastname: Tang
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Kit-San
authors.initials: KS
authors.lastname: Yuen
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Chi-Ping
authors.initials: CP
authors.lastname: Chan
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong dyjin@hku.hk khkok@hku.hk.
authors.forename: Dong-Yan
authors.identifier: http://orcid.org/0000-0002-2778-3530
authors.initials: DY
authors.lastname: Jin
authors.affiliation: Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong dyjin@hku.hk khkok@hku.hk.
authors.forename: Kin-Hang
authors.initials: KH
authors.lastname: Kok
mesh_terms: D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016356:Gene Products, tax; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human
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