Human T cell leukemia virus type I (HTLV-I) is linked to the genesis of adult T cell leukemia (ATL), an aggressive CD4+ T cell malignancy. Tax is an oncoprotein encoded by the HTLV-I genome that regulates viral and cellular gene expression. Tax promotes cell transformation, in part, by activating the NF-kB/Rel transcription factor family. Tax requires NF-kB for the immortalization of primary T cells and HTLV-I transformed cells are dependent on NF-kB for their survival, thereby providing a strong rationale for studying the mechanisms used by Tax to activate NF-kB. Tax activates NF-kB by promoting persistent IkB kinase (IKK) activation although the mechanisms are poorly understood. Our supporting studies indicate that polyubiquitination is a key post- translational regulator of Tax activation of NF-kB. Tax activation of NF-kB correlates with ubiquitin-dependent relocalization of IKK to the Golgi apparatus. Tax is polyubiquitinated via Lys 63-linked ubiquitin chains and requires the ubiquitin conjugating enzyme Ubc13 for Tax ubiquitination and NF-kB activation. Ubiquitination of Tax does not promote its degradation, but rather regulates its interaction with the IKK regulatory subunit IKKg. In addition, we have determined that the Tax interacting cellular protein TAX1BP1 is a key negative regulator of cytokine-mediated NF-kB signaling by functioning as an essential subunit for the ubiquitin-editing enzyme A20. We hypothesize that Tax targets TAX1BP1 as part of a mechanism to promote persistent NF-kB activation. In this proposal, we will further investigate how ubiquitination regulates the targeting of Tax and IKK into the Golgi. We will also further delineate the requirements and the identification of host factors regulating Tax ubiquitination. Finally, we will determine the mechanisms used by Tax to inactivate TAX1BP1 and the A20 ubiquitin-editing complex. Our objectives for this proposal will be satisfied by completion of the following specific aims: (1) Determine the mechanisms of Tax-mediated relocalization of IKK;(2) investigate the molecular determinants of Tax ubiquitination and NF-kB activation and (3) determine the role of Tax binding to TAX1BP1 in NF-kB activation. These studies will shed light on how a retroviral oncoprotein usurps host ubiquitination/deubiquitination machinery to persistently activate transcription factors that promote cell transformation.
The HTLV-I Tax oncoprotein is a potent activator of the NF-kB/Rel transcription factor family. Tax requires NF-kB for the immortalization of T cells, and NF-kB is also required for the survival of HTLV-1 transformed cell lines. The focus of the proposal is to determine the molecular mechanisms used by Tax to activate NF-kB, specifically we will further establish the determinants of Tax ubiquitination and examine the role of Tax interaction with the cellular protein TAX1BP1.
|Choi, Young Bong; Shembade, Noula; Parvatiyar, Kislay et al. (2017) TAX1BP1 Restrains Virus-Induced Apoptosis by Facilitating Itch-Mediated Degradation of the Mitochondrial Adaptor MAVS. Mol Cell Biol 37:|
|Mao, Renfang; Yang, Riyun; Chen, Xia et al. (2017) Regnase-1, a rapid response ribonuclease regulating inflammation and stress responses. Cell Mol Immunol 14:412-422|
|Han, Ke-Jun; Foster, Daniel; Harhaj, Edward W et al. (2016) Monoubiquitination of survival motor neuron regulates its cellular localization and Cajal body integrity. Hum Mol Genet 25:1392-405|
|Bowman, Melissa; Pan, Fan; Harhaj, Edward W (2016) SHARPINing the knowledge of TCR signal control. Nat Immunol 17:221-2|
|Hyun, Jinhee; Ramos, Juan Carlos; Toomey, Ngoc et al. (2015) Oncogenic human T-cell lymphotropic virus type 1 tax suppression of primary innate immune signaling pathways. J Virol 89:4880-93|
|Jain, Pooja; Lavorgna, Alfonso; Sehgal, Mohit et al. (2015) Myocyte enhancer factor (MEF)-2 plays essential roles in T-cell transformation associated with HTLV-1 infection by stabilizing complex between Tax and CREB. Retrovirology 12:23|
|Zhou, Qinjie; Lavorgna, Alfonso; Bowman, Melissa et al. (2015) Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon. J Biol Chem 290:14729-39|
|Shembade, Noula; Harhaj, Edward W (2015) Elucidating dynamic protein-protein interactions and ubiquitination in NF-?B signaling pathways. Methods Mol Biol 1280:283-95|
|Choi, Young Bong; Harhaj, Edward William (2014) Functional implications of mitochondrial reactive oxygen species generated by oncogenic viruses. Front Biol (Beijing) 9:423-436|
|Choi, Young Bong; Harhaj, Edward William (2014) HTLV-1 tax stabilizes MCL-1 via TRAF6-dependent K63-linked polyubiquitination to promote cell survival and transformation. PLoS Pathog 10:e1004458|
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