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Title :HTLV-1 Tax Induces Formation of the Active Macromolecular IKK Complex by Generating Lys63- and Met1-Linked Hybrid Polyubiquitin Chains
Authors :Shibata, Yuri
Tokunaga, Fuminori
Goto, Eiji
Komatsu, Ginga
Gohda, Jin
Saeki, Yasushi
Tanaka, Keiji
Takahashi, Hirotaka
Sawasaki, Tatsuya
Inoue, Satoshi
Oshiumi, Hiroyuki
Seya, Tsukasa
Nakano, Hiroyasu
Tanaka, Yuetsu
Iwai, Kazuhiro
Inoue, Jun-ichiro
Issue Date :19-Jan-2017
Abstract :The Tax protein of human T-cell leukemia virus type 1 (HTLV-1) is crucial for the development of adult T-cell leukemia (ATL), a highly malignant CD4+ T cell neoplasm. Among the multiple aberrant Tax-induced effects on cellular processes, persistent activation of transcription factor NF-κB, which is activated only transiently upon physiological stimulation, is essential for leukemogenesis. We and others have shown that Tax induces activation of the IκB kinase (IKK) complex, which is a critical step in NF-κB activation, by generating Lys63- linked polyubiquitin chains. However, the molecular mechanism underlying Tax-induced IKK activation is controversial and not fully understood. Here, we demonstrate that Tax recruits linear (Met1-linked) ubiquitin chain assembly complex (LUBAC) to the IKK complex and that Tax fails to induce IKK activation in cells that lack LUBAC activity. Mass spectrometric analyses revealed that both Lys63-linked and Met1-linked polyubiquitin chains are associated with the IKK complex. Furthermore, treatment of the IKK-associated polyubiquitin chains with Met1-linked-chain-specific deubiquitinase (OTULIN) resulted in the reduction of high molecular weight polyubiquitin chains and the generation of short Lys63-linked ubiquitin chains, indicating that Tax can induce the generation of Lys63- and Met1-linked hybrid polyubiquitin chains. We also demonstrate that Tax induces formation of the active macromolecular IKK complex and that the blocking of Tax-induced polyubiquitin chain synthesis inhibited formation of the macromolecular complex. Taken together, these results lead us to propose a novel model in which the hybrid-chain-dependent oligomerization of the IKK complex triggered by Tax leads to trans-autophosphorylation-mediated IKK activation.
URL :https://doi.org/10.1371/journal.ppat.1006162
Type Local :雑誌掲載論文
ISSN :1553-7374
Publisher :Public Library of Science
URI :http://hdl.handle.net/20.500.12000/45642
Citation :PLOS Pathogens Vol.13 no.1
Appears in Collections:Peer-reviewed Journal Articles (Faculty of Medicine)

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