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PLoS Pathog. 2017 Jan 19;13(1):e1006162. doi: 10.1371/journal.ppat.1006162. eCollection 2017 Jan.

HTLV-1 Tax Induces Formation of the Active Macromolecular IKK Complex by Generating Lys63- and Met1-Linked Hybrid Polyubiquitin Chains.

Author information

1
Division of Cellular and Molecular Biology, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
2
Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, Japan.
3
Research Center for Asian Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
4
Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
5
Proteo-Science Center, Ehime University, Ehime, Japan.
6
Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
7
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
8
Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan.
9
Division of Immunology, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
10
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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.

PMID:
28103322
PMCID:
PMC5283754
DOI:
10.1371/journal.ppat.1006162
[Indexed for MEDLINE]
Free PMC Article

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