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Titration of cellular export factors, but not heteromultimerization, is the molecular mechanism of trans-dominant HTLV-1 Rex mutants

Oncogene volume 18, pages 4080–4090 (1999)Cite this article

Abstract

The HTLV-1 Rex protein is an essential shuttle protein required for nuclear export of unspliced and incompletely-spliced viral RNAs. Several trans-dominant (TD) mutant Rex proteins have been reported, however, the mechanism of trans-dominance is not known. We compared TD Rex mutants and found that a natural occurring Rex mutant, Rexp21, lacking the RNA binding domain, was highly TD and inhibited also HIV-1 Rev function. Using fusions to the green fluorescent protein (GFP) we observed that Rexp21-GFP displayed a cytoplasmic localization but was actively shuttling between the nucleus and the cytoplasm in live human cells. The presence of Rexp21-GFP inhibited the nuclear export of Rex and HIV-1 Rev as assayed by cotransfection and microinjection experiments. However, Rex-GFP or Rexp21-GFP did not form heteromultimers with nuclear Rex mutants in vivo. In contrast, shuttling was essential for trans-dominance. Thus, we propose that TD Rex mutants do not function by retaining WT Rex in the nucleus by protein-protein interactions, as demonstrated for Rev, but to titrate factors essential for Rex/Rev export. Our findings demonstrate differences between the regulatory proteins Rex and Rev and implicate a novel strategy to generate highly TD Rex mutants also applicable to other proteins.

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References

  • Adachi Y, Copeland TD, Takahashi C, Nosaka T, Ahmed A, Oroszlan S and Hatanaka M. . 1992 J. Biol. Chem. 267: 21977–21981.

  • Bakker A, Li X, Ruland CT, Stephens DW, Black AC and Rosenblatt JD. . 1996 J. Virol. 70: 5511–5518.

  • Berneman ZN, Gartenhaus RB, Reitz MS, Blattner WA, Manns A, Hanchard B, Ikehara O, Gallo RC and Klotman ME. . 1992 Proc. Natl. Acad. Sci. USA 89: 3005–3009.

  • Bhat NK, Adachi Y, Samuel KP and Derse D. . 1993 Virology 196: 15–24.

  • Black AC, Chen ISY, Arrigo S, Ruland CT, Allogiamento T, Chin E and Rosenblatt JD. . 1991 Virology 181: 433–444.

  • Black AC, Ruland CT, Luo J, Bakker A, Fraser JK and Rosenblatt JD. . 1994 Virology 200: 29–41.

  • Bogerd H and Greene WC. . 1993 J. Virol. 67: 2496–2502.

  • Bogerd HP, Huckaby GL, Ahmed YF, Hanly SM and Greene WC. . 1991 Proc. Natl. Acad. Sci. USA 88: 5704–5708.

  • Bogerd HP, Fridell RA, Benson RE, Hua J and Cullen BR. . 1996 Mol. Cell Biol. 16: 4207–4214.

  • Bogerd HP, Echarri A, Ross TM and Cullen BR. . 1998 J. Virol. 72: 8627–8635.

  • Böhnlein E, Berger J and Hauber J. . 1991a J. Virol. 65: 7051–7055.

  • Böhnlein S, Pirker F, Hofer L, Zimmermann K, Bachmayer H, Böhnlein E and Hauber J. . 1991b J. Virol. 65: 81–88.

  • Cann AJ, Rosenblatt JD, Wachsman W, Shah NP and Chen ISY. . 1985 Nature (London) 318: 571–574.

  • Ciminale V, Zotti L, D'Agostino DM and Chieco-Bianchi L. . 1997 J. Virol. 71: 2810–2818.

  • Cullen BR. . 1992 Microbiol. Rev. 56: 375–394.

  • DeThe G and Bomford R. . 1993 AIDS Res. Hum. Retroviruses 9: 381–386.

  • Essex M, Matsuda Z, Yu X and Lee TH. . 1995 Leukemia 9: S71–S74.

  • Felber B, Paskalis H, Kleinman-Ewing C, Wong-Staal F and Pavlakis G. . 1985 Science 229: 675–679.

  • Felber BK. . 1997 mRNA metabolism and post-transcriptional gene regulation pp 323–340, Wiley-Liss, Inc.

    Google Scholar 

  • Fornerod M. . 1997 EMBO J. 16: 807–816.

  • Fornerod M, Ohno M, Yoshida M and Mattaj IW. . 1997 Cell 90: 1051–1060.

  • Fukuda M, Asano S, Nakamura T, Adachi M, Yoshida M, Yanagida M and Nishida E. . 1997 Nature (London) 390: 308–311.

  • Furuta RA, Kubota S, Maki M, Miyazaki Y, Hattori T and Hatanaka M. . 1995 J. Virol. 69: 1591–1599.

  • Gessain A, Barin F, Vernant JC, Gout O, Maurs L, Calender A and deThe G. . 1985 Lancet 2: 407–410.

  • Gitlin SD, Dittmer J, Reid RL and Brady JN. . 1993 The molecular biology of human T-cell leukemia viruses, Oxford University Press, Oxford.

    Google Scholar 

  • Gorlich D. . 1997 Curr. Opin. Cell Biol. 9: 412–419.

  • Gorlich D. . 1998 EMBO J. 17: 2721–2727.

  • Grassmann R, Berchtold S, Aepinus C, Ballaun C, Böhnlein E and Fleckenstein B. . 1991 J. Virol. 65: 3721–3727.

  • Gröne M, Koch C and Grassmann R. . 1996 Virology 218: 316–325.

  • Hakata Y, Umemoto T, Matsushita S and Shida H. . 1998 J. Virol. 72: 6602–6607.

  • Hammarskjöld ML. . 1997 Sem. Cell Develop. Biol. 63: 83–90.

  • Hammes SR and Greene WC. . 1993 Virology 193: 41–49.

  • Heger P, Rosorius O, Koch C, Casari G, Grassmann R and Hauber J. . 1998 J. Virol. 72: 8659–8668.

  • Henderson BR and Percipalle P. . 1997 J. Mol. Biol. 274: 693–707.

  • Hidaka M, Inoue J, Yoshida M and Seiki M. . 1988 EMBO J. 7: 519–523.

  • Hinuma Y, Nagata K, Hanaoka M, Nakai M, Matsumoto T, Kinoshita I, Shirakawa S and Miyoshi I. . 1981 Proc. Natl. Acad. Sci. USA 78: 6476–6480.

  • Hofer L, Weichselbraun I, Quick S, Farrington G, Böhnlein E and Hauber J. . 1991 J. Virol. 65: 3379–3383.

  • Hope TJ, Klein NP, Elder ME and Parslow TG. . 1992 J. Virol. 66: 1849–1855.

  • Inoue J, Seiki M, Taniguchi T, Tsuru S and Yoshida M. . 1986 EMBO J. 5: 2883.

  • Jäkel S and Görlich D. . 1998 EMBO J. 17: 4491–4502.

  • Kanamori H, Suzuki N, Siomi H, Nosaka T, Sato A, Sabe H, Hatanaka M and Honjo T. . 1990 EMBO J. 9: 4161–4166.

  • Katahira J, Ishizaki T, Adachi A, Yamamoto K and Shida H. . 1995 J. Virol. 69: 3125–3133.

  • Kim FJ, Beeche AA, Hunter JJ, Chin DJ and Hope TJ. . 1996 Mol. Cell Biol. 16: 5147–5155.

  • King JA, Bridger JM, Löchelt M, Lichter P, Schulz TF, Schirrmacher V and Khazaie K. . 1998 Oncogene 16: 3309–3316.

  • Kiyokawa T, Seiki M, Iwashita S, Imagawa K, Shimizu F and Yoshida M. . 1985 Proc. Natl. Acad. Sci. USA 82: 8359–8363.

  • Kubota S, Nosaka T, Cullen BR, Maki M and Hatanaka M. . 1991 J. Virol. 65: 2452–2456.

  • Kubota S, Furuta R, Maki M and Hatanaka M. . 1992 J. Virol. 66: 2510–2513.

  • Kubota S, Hatanaka M and Pomerantz RJ. . 1996 Virology 220: 502–507.

  • Lagrenade L, Hanchard B, Fletcher V, Cranston B and Blattner W. . 1990 Lancet 336: 1345–1347.

  • Malim MH, Böhnlein S, Hauber J and Cullen BR. . 1989 Cell 58: 205–214.

  • Malim MH and Cullen BR. . 1991 Cell 65: 241–248.

  • McGuire KL, Curtiss VE, Larson EL and Haseltine WA. . 1993 J. Virol. 67: 1590–1599.

  • Morgan O, Rodgers-Johnson P, Mora C and Char G. . 1989 Lancet ii: 1184–1186.

  • Murai K, Tachibana N, Shioiri S, Shishime E, Okayama A, Ishizaki J, Tsuda K and Mueller N. . 1990 J Acquir. Immune. Defic. Syndr. 3: 1006–1009.

  • Nakielny S and Dreyfuss G. . 1996 J. Cell Biol. 134: 1365–1373.

  • Nosaka T, Siomi H, Adachi Y, Ishibashi M, Kubota S, Maki M and Hatanaka M. . 1989 Proc. Natl. Acad. Sci. USA 86: 9798–9802.

  • Orita S, Saiga A, Takagi S, Tanaka I, Okumura K, Aono Y, Hinuma Y and H I. . 1991 FEBS Letters 295: 127–134.

  • Ossareh-Nazari B, Bachelerie F and Dargemont C. . 1997 Science (Washington DC) 278: 141–144.

  • Palmeri D and Malim MH. . 1996 J. Virol. 70: 6442–6445.

  • Park MH, Wolff EC and Folk JE. . 1993a BioFactors 4: 95–104.

  • Park MH, Wolff EC and Folk JE. . 1993b TIBS 18: 475–479.

  • Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD and Gallo RC. . 1980 Proc. Natl. Acad. Sci. USA 77: 7415–7419.

  • Pollard VW and Malim MH. . 1998 Annu. Rev. Microbiol. (In press).

  • Rimsky L, Duc Dodon M, Dixon EP and Greene WC. . 1989 Nature 341: 453–456.

  • Rosorius O, Reichart B, Krätzer F, Heger P, Dabauvalle M-C and Hauber J. . 1998 submitted.

  • Schmidt-Zachmann MS, Dargemont C, Kuehn L and Nigg EA. . 1993 Cell 74: 493–504.

  • Siomi H, Shida H, Nam SH, Nosaka T, Maki M and Hatanaka M. . 1988 Cell 55: 197–209.

  • Smith MR and Greene WC. . 1991 J. Clin. Invest. 87: 761–766.

  • Sodroski J, Rosen C, Goh WC and Haseltine W. . 1985 Science (Washington DC) 228: 1430–1434.

  • Stade K, Ford CS, Guthrie C and Weis K. . 1997 Cell 90: 1041–1050.

  • Stauber R, Gaitanaris GA and Pavlakis GN. . 1995 Virology 213: 439–449.

  • Stauber RH, Afonina E, Gulnik S, Erickson J and Pavlakis GN. . 1998a Virology 251: 38–48.

  • Stauber RH, Horie K, Carney P, Hudson EA, Tarasova NI, Gaitanaris GA and Pavlakis GN. . 1998b Biotechniques 24: 462–471.

  • Stauber RH and Pavlakis GN. . 1998 Virology 252: 126–132.

  • Szilvay AM, Brokstad KA, Kopperud R, Haukenes G and Kalland KH. . 1995 J. Virol. 69: 3315–3323.

  • Thomas SL, Oft M, Jaksche H, Casari G, Heger P, Dobrovnik M, Bevec D and Hauber J. . 1998 J. Virol. 72: 2935–2944.

  • Uchiyama T. . 1997 Annu. Rev. Immunol. 15: 15–37.

  • Weichselbraun I, Berger J, Dobrovnik M, Bogerd H, Grassmann R, Greene W, Hauber J and Böhnlein E. . 1992a J. Virol. 66: 4540–4545.

  • Weichselbraun I, Farrington G, Rusche J, Böhnlein E and Hauber J. . 1992b J. Virol. 66: 2583–2587.

  • Wolff B, Sanglier J-J and Wang Y. . 1997 Chem. Biol. 4: 139–147.

  • Yoshida M, Miyoshi I and Hinuma Y. . 1982 Proc.Natl. Acad. Sci. USA 79: 2031.

  • Yoshida M. . 1996 J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 13: 63–68.

  • Zolotukhin AS and Felber BK. . 1999 J. Virol. 73: 120–127.

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Acknowledgements

We thank R Hudson for confocal microscopy, G Pavlakis for the HLtat cell line and N Hirschmann for excellent technical assistance. Leptomycin B was kindly provided by the Novartis Research Institute Vienna. R Stauber is supported by the DKFZ AIDS-Stipendium Program. This work was supported by the Deutsche Forschungsgemeinschaft (SFB466).

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  1. Institute for Medical and Clinical Virology, University of Erlangen-Nürnberg, Schlossgarten 4, Erlangen, D-91054, Germany

    Peter Heger, Olaf Rosorius, Joachim Hauber & Roland H Stauber

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Heger, P., Rosorius, O., Hauber, J. et al. Titration of cellular export factors, but not heteromultimerization, is the molecular mechanism of trans-dominant HTLV-1 Rex mutants. Oncogene 18, 4080–4090 (1999). https://doi.org/10.1038/sj.onc.1202762

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