title: HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains.
abstract: The HTLV-1 oncoprotein Tax plays a key role in CD4+ T cell transformation by promoting cell proliferation and survival, mainly through permanent activation of the NK-κB pathway and induction of many NF-κB target genes. Elucidating the underlying molecular mechanism is therefore critical in understanding HTLV-1-mediated transformation. Current studies have suggested multiple but controversial mechanisms regarding Tax-induced IKK activation mainly due to blending of primary Tax-induced IKK activation events and secondary IKK activation events induced by cytokines secreted by the primary Tax-induced IKK-NF-κB activation events. We reconstituted Tax-stimulated IKK activation in a cell-free system to dissect the essential cellular components for primary IKK activation by Tax and studied the underlying biochemical mechanism. We found that Tax is a putative E3 ubiquitin ligase, which, together with UbcH2, UhcH5c, or UbcH7, catalyzes the assembly of free mixed-linkage polyubiquitin chains. These free mixed-linkage polyubiquitin chains are then responsible for direct IKK activation by binding to the NEMO subunit of IKK. Our studies revealed the biochemical function of Tax in the process of IKK activation, which utilizes the minimal cellular ubiquitination components for NF-κB activation.
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Wenying
authors.initials: W
authors.lastname: Long
authors.affiliation: National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Peng
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Hu
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Ailing
authors.initials: A
authors.lastname: Wu
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Duan
authors.affiliation: National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Catherine C L
authors.initials: CC
authors.lastname: Wong
authors.affiliation: Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Nishihara-cho, Okinawa, Japan.
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Zongping
authors.initials: Z
authors.lastname: Xia
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004789:Enzyme Activation / Q000502:physiology*; D055786:Gene Knockout Techniques; D016356:Gene Products, tax / Q000378:metabolism*; D057809:HEK293 Cells; D015490:HTLV-I Infections / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D015151:Immunoblotting; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism; D025821:Polyubiquitin / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology; D053719:Tandem Mass Spectrometry; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D016356:Gene Products, tax; D016328:NF-kappa B; C514970:tax protein, Human T-lymphotrophic virus 1; D025821:Polyubiquitin; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase