HTLV-1 Tax Induces Formation of the Active Macromolecular IKK Complex by Generating Lys63- and Met1-Linked Hybrid Polyubiquitin Chains.
In: PLoS Pathogens, Jg. 13 (2017-01-19), Heft 1, S. 1-25
Online
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Zugriff:
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. [ABSTRACT FROM AUTHOR]
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HTLV-1 Tax Induces Formation of the Active Macromolecular IKK Complex by Generating Lys63- and Met1-Linked Hybrid Polyubiquitin Chains.
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Autor/in / Beteiligte Person: | 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 |
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Zeitschrift: | PLoS Pathogens, Jg. 13 (2017-01-19), Heft 1, S. 1-25 |
Veröffentlichung: | 2017 |
Medientyp: | academicJournal |
ISSN: | 1553-7366 (print) |
DOI: | 10.1371/journal.ppat.1006162 |
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