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Jacob AlSaleem Disseration.pdf (4.84 MB)

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Identification of HTLV-1 Tax-1 and HBZ Binding Partners, and Their Role in HTLV-1 Biology and Pathogenesis

Al-Saleem, Jacob Jamal
http://orcid.org/0000-0001-8929-7098
http://rave.ohiolink.edu/etdc/view?acc_num=osu1479901289612684

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Human T cell Leukemia Virus type 1 (HTLV-1) is estimated to have infected 15-20 million individuals world-wide. A subgroup of infected individuals develop diseases associated with viral infection, which include adult T cell leukemia and HTLV-1 associated myelopathy/tropic spastic paraparesis. A closely related virus, HTLV-2, shares 70% nucleotide similarity with HTLV-1, but is not associated with any disease. Previous research has demonstrated that Tax-1 serves as the primary oncoprotein of HTLV-1, and its deletion or functional disruption completely ablates the transforming capacity of HTLV-1. Tax-2 (HTLV-2) has been demonstrated to have lower transforming capabilities than Tax-1. These differences are attributed to two domains present in Tax-1 yet absent in Tax-2; the four-amino acid PDZ binding motif (PBM) and an eight-amino acid leucine zipper-like region (LZ). These domains have been demonstrated to be required for the ability of Tax-1 to activate the alternative NF-κB pathway. Chapter Two of this dissertation analyzes the role that the alternative NF-κB pathway plays in HTLV-1 mediated T cell transformation. Analysis of the Tax-1 PBM or LZ mutants revealed that deletion of the PBM does not inhibit activation of the alternative NF-κB pathway. We then show that the PBM domain is required for Tax-1 activation of Akt signaling, and the mechanism behind this activation involves interactions between Tax-1, DLG-1, and PTEN. The Tax-1 LZ domain is required for activation of alternative NF-κB and HTLV-1 featuring the mutated Tax-1 LZ transformed T cells with an efficiency similar to wild type virus. This is the first evidence suggesting that alternative NF-κB activity is not required for in vitro cellular transformation of primary T-lymphocytes in culture. Studies in Chapter Three focus on dissecting the mechanism for Tax-1 activation of the alternative NF-κB pathway. Binding partners of four different Tax constructs were identified, including a mutant incapable of activating alternative NF-κB. While six proteins were identified as potentially important for alternative NF-κB activation, none passed initial screening to confirm their interaction profile. Other novel interactions of Tax-1 were analyzed, and an interaction between Tax-1 and SNX27 was discovered. We demonstrated that, through SNX27, Tax-1 regulates the localization of the HTLV-1 receptor molecule GLUT1. This is the first report describing a mechanism by which HTLV-1 regulates its receptor molecule. HTLV-1 expresses HBZ from the antisense strand of the viral genome. Both HBZ protein and mRNA have been implicated to promote proliferation of T cells. Studies in Chapter Four focused on investigating the mechanism behind these proliferative effects. Binding partners of both HBZ protein and mRNA were identified and analyzed to uncover interactions that regulate proliferation. Our preliminary experiments have identified cellular candidates that bind the HBZ protein and mRNA, but to date we have yet to identify a functional interacting partner. Further analysis is on-going. Collectively the data in this dissertation demonstrates that activation of the alternative NF-κB pathway is dispensable for in vitro transformation of T cells, and identifies binding partners of both Tax-1 and HBZ. Tax-1 activation of Akt was found to be dependent on the PBM, and this activation may serve as a therapeutic target. The interaction between Tax-1 and SNX27 could have profound implications on HTLV-1 biology as it is the first identified method of HTLV-1 regulation of receptor molecules post-entry. Several binding partners of both HBZ protein and mRNA were discovered, and follow up studies will be required to identify the role these interactions may play in HTLV-1 biology and pathogenesis.
Patrick Green, Ph.D (Advisor)
Jesse Kwiek, Ph.D (Committee Member)
Li Wu, Ph.D (Committee Member)
Stefan Niewiesk, DVM, Ph.D (Committee Member)
197 p.
Molecular Biology; Virology
HTLV-1; HTLV-2; ATL; HAM-TSP; SNX27; NF-kB; Tax-1; HBZ

Recommended Citations

Citations

  • Al-Saleem, J. J. (2016). Identification of HTLV-1 Tax-1 and HBZ Binding Partners, and Their Role in HTLV-1 Biology and Pathogenesis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1479901289612684

    APA Style (7th edition)

  • Al-Saleem, Jacob. Identification of HTLV-1 Tax-1 and HBZ Binding Partners, and Their Role in HTLV-1 Biology and Pathogenesis. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1479901289612684.

    MLA Style (8th edition)

  • Al-Saleem, Jacob. "Identification of HTLV-1 Tax-1 and HBZ Binding Partners, and Their Role in HTLV-1 Biology and Pathogenesis." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1479901289612684

    Chicago Manual of Style (17th edition)

osu1479901289612684
657
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This open access ETD is published by The Ohio State University and OhioLINK.