Human T cell leukemia virus type I (HTLV-I) has been linked to the development of an aggressive lymphoproliferative disorder (adult T cell leukemia), a chronic neurodegenerative presentation (HTLV-I-associated myelopathy/tropical spastic paraparesis) and numerous less well-defined inflammatory conditions. The viral regulatory protein Tax has been implicated in cellular transformation events leading to the onset of adult T cell leukemia. Details on the stepwise processes through which Tax induces morphological changes in cells are poorly understood. We show here that Tax can bind to a class of intermediate filaments, the cytokeratins (Ker). Tax interacts with the 1B helical coil of keratin 8, a domain critical for higher-order intermediate filament matrix formation. Expression of Tax in epithelial cells visibly altered the structural pattern of the Ker network. In a T lymphocyte cell line, induction of Tax expression resulted in increased cellular adherence/invasion of Matrigel filters. We propose that one aspect of Tax function is the induction of morphological changes in cellular cytoskeletal structures. This finding for Tax-expressing cells might be one factor contributing directly to the pathogenesis of HTLV-I disease(s).
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Adya N, Giam CZ. Distinct regions in human T-cell lymphotropic virus type I Tax mediate interactions with activator protein CREB and basal transcription factors. J Virol 69:1834–1841;1995.
Albers K, Fuchs E. The molecular biology of intermediate filament proteins. Int Rev Cytol 134:243–279;1992.
Beraud C, Sun S-C, Ganchi P, Ballard DW, Greene WC. Human T-cell leukemia virus type I Tax associates with and is negatively regulated by the NF-kB2 p100 gene product: Implications for viral latency. Mol Cell Biol 14:1374–1382;1994.
Cann AJ, Rosenblatt JD, Wachsman W, Shah NP, Chen IS. Identification of the gene responsible for human T-cell leukemia virus transcriptional regulation. Nature 318:571–574;1985.
Carmo-Fonseca M, David-Ferreira JF. Interactions of intermediate filaments with cell structures. Electron Microsc Rev 3:115–141;1990.
Chan YM, Antonlamprecht I, Yu QC, Jackel A, Zabel B, Ernst JP, Fuchs E. A human keratin-14 knockout: The absence of K14 leads to severe epidemolysis-bullosa simplex and a function for an intermediate filament protein. Genes Dev 8:2574–2587;1994.
Chu Y-W, Runyan RB, Oshima RG, Hendrix MJC. Expression of complete keratin filaments in mouse L cells augments cell migration and invasion. Proc Natl Acad Sci USA 90:4261–4265;1993.
Coulombe PA, Hutton ME, Letai A, Hebert A, Paller AS, Fuchs E. Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: Genetic and functional analysis. Cell 66:1301–1311;1991.
Dhawan S, Weeks BS, Abbasi F, Gralnick HR, Notkins AL, Klotman ME, Yamada KM, Klotman PE. Increased expression of a4b1 and a5b1 integrins on HTLV-I-infected lymphocytes. Virology 197:778–781;1993.
Doorbar J, Ely S, Sterling J, McLean C, Crawford L. Specific interaction between HPV-16 E1-E4 and cytokeratins results in collapse of the epithelial cell intermediate filament network. Nature 352:824–827;1991.
Felber BK, Paskalis H, Kleinman-Ewing C, Wong-Staal F, Pavlakis GN. The pX protein of HTLV I is a transcriptional activator of its long terminal repeats. Science 229:675–679;1985.
Feuer G, Chen IS. Mechanisms of human T-cell leukemia virus-induced leukemogenesis. Biochim Biophys Acta 1114:223–233;1992.
Franklin AA, Nyborg JK. Mechanisms of Tax regulation of human T cell leukemia virus type I gene expression. J Biomed Sci 2:17–29;1995.
Fujii M, Chuhjo T, Minamino T, Masaahi N, Miyamoto K, Seiki M. Identification of the Tax interaction domain region of serum response factors that mediate aberrant induction of immediate early genes through CArG boxes by HTLV-I Tax. Oncogene 11:7–14;1995.
Fujisawa J, Seiki M, Kiyokawa T, Yoshida M. Functional activation of the long terminal repeat of human T-cell leukemia virus type I by a trans-acting factor. Proc Natl Acad Sci USA 82:2277–2281;1985.
Good L, Sun S-C. Persistent activation of NF-κB/Rel by human T-cell leukemia virus type 1 Tax involves degradation of IκBb. J Virol 70:2730–2735;1996.
Goren I, Semmes OJ, Jeang K-T, Moelling K. Amino terminus of Tax is required for interaction with CREB. J Virol 69:5806–5811;1995.
Graham FL, van der Eb AJ. Transformation of rat cells by DNA of human adenovirus 5. Virology 54:536–539;1973.
Hirai H, Fujisawa J-I, Suzuki K, Ueda K, Muramutsu M, Tsuboi A, Arai N, Yoshida M. Transcriptional activator Tax of HTLV-1 binds to the NF-κB precursor p105. Oncogene 7:1737–1742;1992.
Ijichi S, Izumo S, Eiraku N, Machigashira K, Kubota R, Nagai M, Ikegami N, Kashio N, Umehara F, Marutama I, Osame M. An autoaggressive process against bystander tissues in HTLV-I-infected individuals: A possible pathomechanism of HAM/TSP. Med Hypotheses 41:542–547;1993.
Jeang K-T, Widen SG, Semmes OJ, Wilson SH. HTLV-I trans-activator protein, Tax, is a trans-repressor of the human beta-polymerase gene. Science 247:1082–1084;1990.
Kitajima I, Kawahara K, Hanyu N, Shin H, Tokioka T, Soejima Y, Tsutsui J, Ozawa M, Shimayama T, Maruyama I. Enhanced E-cadherin expression and increased calcium-dependent cell-cell adhesion in human T-cell leukemia virus type I Tax-expressing PC12 cells. J Cell Sci 109:609–617;1996.
Lacoste J, Petropoulos L, Pepin N, Hiscott J. Constitutive phosphorylation and turnover of IκBa in human T-cell leukemia virus type I-infected and Tax-expressing T cells. J Virol 69:564–569;1995.
Lanoix J, Lacoste J, Pepin N, Rice NR, Hiscott J. Overproduction of NFκB2 (lyt-10) and c-rel: A mechanism for HTLV-1 Tax-mediated trans-activation via the NF-κB signaling pathway. Oncogene 9:841–852;1994.
Liebowitz D, Kopan R, Fuchs E, Sample J, Kieff E. An Epstein-Barr virus transforming protein associates with vimentin in lymphocytes. Mol Cell Biol 7:2299–2308;1987.
Maggirwar SB, Harhaj E, Sun SC. Activation of NF-κB/Rel by Tax involves degradation of IκBa and is blocked by a proteosome inhibitor. Oncogene 11:993–998;1995.
Majone F, Semmes OJ, Jeang K-T. Induction of micronuclei by HTLV-I Tax: A cellular assay for function. Virology 193:456–459;1993.
McCormick MB, Coulombe PA, Fuchs E. Sorting out IF networks: Consequences of domain swapping on IF recognition and assembly. J Cell Biol 113:1111–1114;1991.
Murakami T, Hirai H, Suzuki T, Fujisawa J-I, Yoshida M. HTLV-I Tax enhances NF-κB2 expression and binds to the products p52 and p100, but does not suppress the inhibitory function of p100. Virology 206:1066–1074;1995.
Nagata K, Ohtani K, Nakamura M, Sugamura K. Activation of endogenous c-fos prot-oncogene expression by human T-cell leukemia virus type I-encoded p40tax protein in the human T-cell line, Jukat. J Virol 63:3220–3226;1989.
Osame H, Ijichi S. Benign monoclonal T-cell proliferation in HTLV-I infection. Med Hypotheses 41:363–368;1993.
Pepin N, Roulston A, Lacoste J, Lin R, Hiscott J. Subcellular redistribution of HTLV-1-Tax protein by NF-κB/Rel transcription factors. Virology 204:706–716;1994.
Rugg EL, Mclean WHI, Lane EB, Pitera R, Mcmillan JR, Doppinghepenstal PJC, Navsaria HA, Leigh IM, Eady RAJ. A functional knockout of human keratin-14. Genes Dev 8:2563–2573;1994.
Salvetti A, Lilienbaum A, Portier MM, Guonon P, Paulin D, Gazzolo L. Organization and expression of intermediate filaments in epithelial cells expressing the HTLV-I Tax protein. Eur J Cell Biol 61:383–391;1993.
Schwartz SM, Gallicano GI, McGaughey RW, Capco DG. A role for intermediate filaments in the establishment of the primitive epithelia during mammalian embryogenesis. Mech Dev 53:305–321;1995.
Semmes OJ, Jeang K-T. HTLV-I Tax is a zinc-binding protein: Role of zinc in Tax structure and function. Virology 188:754–764;1990.
Semmes OJ, Jeang K-T. Mutational analysis of human T-cell leukemia virus type I ax: Regions necessary for function determined with 47 mutant proteins. J Virol 66:7183–7192;1992.
Semmes OJ, Jeang K-T. Definition of a minimal activation domain in human T-cell leukemia virus type I Tax. J Virol 69:1827–1833;1995.
Semmes OJ, Barrett JF, Dang CV, Jeang K-T, Human T-cell leukemia virus type I masks c-Myc function through a cAMP-dependent pathway. J Biol Chem 271:9730–9738;1996.
Semmes OJ, Jeang K-T. Localization of human T-cell leukemia virus type 1 Tax to subnuclear compartments that overlap with interchromatin speckles. J Virol 70:6347–6357;1996.
Smith MR, Green WC. Molecular biology of the type I human T-cell leukemia virus (HTLV-I) and adult T-cell leukemia. J Clin Invest 87:761–766;1991.
Smith MR, Greene WC. Characterization of a novel nuclear localization signal in the HTLV-I Tax transactivator protein. Virology 187:316–320;1990.
Sodroski JG, Rosen CA, Haseltine WA. A transcriptional activator protein encoded by the x-lor region of the human T-cell leukemia virus. Science 225:381–385;1986.
Sodroski J. The human T-cell leukemia virus (HTLV) transactivator (Tax) protein. Biochim Biophys Acta 1114:19–29;1992.
Suzuki T, Hirai H, Fujisawa J, Fujita T, Yoshida M. A transactivator Tax of human T-cell leukemia virus type 1 binds to NF-kappa B p50 and serum response factor (SRF) and associates with enhancer DNAs of the NF-kappa B site and CArG Box. Oncogene 8:2391–2397;1993.
Suzuki T, Hirai H, Yoshida M. Tax protein of HTLV-I interacts with the Rel homology domain of NF-κB binding site and activates transcription. Oncogene 9:3099–3105;1994.
Troyanovsky SM, Eshkind L, Troyanovsky RB, Leube RE, Franke WW. Contributions of cytoplasmic domains of desmosomal cadherins to desmosome assembly and intermediate filament anchorage. Cell 72:561–574;1993.
Vassar R, Coulombe PA, Degenstein L, Albers K, Fuchs E. Mutant keratin expression in transgenic mice causes marked abnormalities resembling a human genetic skin disease. Cell 64:365–380;1991.
Watanabe M, Muramatsu M, Hirai H, Suzuki T, Fujisawa J-I, Yoshida M, Arai K-I, Arai N. HTLV-I encoded Tax in association with NF-κB precursor p105 enhances nuclear localization of NF-κB p50 and p65 in transfected cells. Oncogene 8:2949–2958;1993.
White E, Cipriani R. Role of adenovirus E1B proteins in transformation: Altered organization of intermediate filaments in transformed cells that express the 19-kilodalton protein. Mol Cell Biol 10:120–130;1990.
Yin MJ, Paulssen EJ, Seeler JS, Gaynor RB. Protein domains involved in both in vivo and in vitro interactions between human T-cell leukemia virus type I Tax and CREB. J Virol 69:3420–3432;1995.
Yoshida M. HTLV-I Tax: Regulation of gene expression and disease. Trends Microbiol 1:131–135;1993.
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Trihn, D., Jeang, K. & Semmes, O.J. HTLV-I tax and cytokeratin: Tax-expressing cells show morphological changes in keratin-containing cytoskeletal networks. J Biomed Sci 4, 47–53 (1997). https://doi.org/10.1007/BF02255593
- Regulatory protein