Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1994 Nov;14(11):7436–7444. doi: 10.1128/mcb.14.11.7436

The human immunodeficiency virus type 1 Rev protein shuttles between the cytoplasm and nuclear compartments.

K H Kalland 1, A M Szilvay 1, K A Brokstad 1, W Saetrevik 1, G Haukenes 1
PMCID: PMC359279  PMID: 7935458

Abstract

A retroviral regulatory protein, Rev (regulator of virion protein expression), is made in cells infected by human immunodeficiency virus (HIV). Rev is essential for the completion of the retroviral life cycle and interacts with the host cell at some posttranscriptional step in order to express the incompletely spliced HIV mRNAs from which HIV structural proteins are translated. Neither the host cell components nor the mechanisms responsible for this important regulation have been defined. We now report that Rev is a nucleocytoplasmic shuttle protein which is continuously transported between the cytoplasm, the nucleoli, and nucleoplasmic speckles enriched in RNA splicing and processing factors. The results show that Rev has the potential to interfere specifically with the splicing of the HIV pre-mRNA in the nucleoplasm and, next, guide such mRNAs to the cytoplasm for translation.

Full text

PDF
7439

Images in this article

7438Image
on p.7438
7439Image
on p.7439
7440Image
on p.7440
7441Image
on p.7441
7442Image
on p.7442

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arrigo S. J., Chen I. S. Rev is necessary for translation but not cytoplasmic accumulation of HIV-1 vif, vpr, and env/vpu 2 RNAs. Genes Dev. 1991 May;5(5):808–819. doi: 10.1101/gad.5.5.808. [DOI] [PubMed] [Google Scholar]
  2. Bochnig P., Reuter R., Bringmann P., Lührmann R. A monoclonal antibody against 2,2,7-trimethylguanosine that reacts with intact, class U, small nuclear ribonucleoproteins as well as with 7-methylguanosine-capped RNAs. Eur J Biochem. 1987 Oct 15;168(2):461–467. doi: 10.1111/j.1432-1033.1987.tb13439.x. [DOI] [PubMed] [Google Scholar]
  3. Borer R. A., Lehner C. F., Eppenberger H. M., Nigg E. A. Major nucleolar proteins shuttle between nucleus and cytoplasm. Cell. 1989 Feb 10;56(3):379–390. doi: 10.1016/0092-8674(89)90241-9. [DOI] [PubMed] [Google Scholar]
  4. Bray M., Prasad S., Dubay J. W., Hunter E., Jeang K. T., Rekosh D., Hammarskjöld M. L. A small element from the Mason-Pfizer monkey virus genome makes human immunodeficiency virus type 1 expression and replication Rev-independent. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1256–1260. doi: 10.1073/pnas.91.4.1256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carmo-Fonseca M., Pepperkok R., Sproat B. S., Ansorge W., Swanson M. S., Lamond A. I. In vivo detection of snRNP-rich organelles in the nuclei of mammalian cells. EMBO J. 1991 Jul;10(7):1863–1873. doi: 10.1002/j.1460-2075.1991.tb07712.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Carmo-Fonseca M., Tollervey D., Pepperkok R., Barabino S. M., Merdes A., Brunner C., Zamore P. D., Green M. R., Hurt E., Lamond A. I. Mammalian nuclei contain foci which are highly enriched in components of the pre-mRNA splicing machinery. EMBO J. 1991 Jan;10(1):195–206. doi: 10.1002/j.1460-2075.1991.tb07936.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carter K. C., Taneja K. L., Lawrence J. B. Discrete nuclear domains of poly(A) RNA and their relationship to the functional organization of the nucleus. J Cell Biol. 1991 Dec;115(5):1191–1202. doi: 10.1083/jcb.115.5.1191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chang D. D., Sharp P. A. Regulation by HIV Rev depends upon recognition of splice sites. Cell. 1989 Dec 1;59(5):789–795. doi: 10.1016/0092-8674(89)90602-8. [DOI] [PubMed] [Google Scholar]
  9. Choi Y. D., Dreyfuss G. Monoclonal antibody characterization of the C proteins of heterogeneous nuclear ribonucleoprotein complexes in vertebrate cells. J Cell Biol. 1984 Dec;99(6):1997–1204. doi: 10.1083/jcb.99.6.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cochrane A. W., Jones K. S., Beidas S., Dillon P. J., Skalka A. M., Rosen C. A. Identification and characterization of intragenic sequences which repress human immunodeficiency virus structural gene expression. J Virol. 1991 Oct;65(10):5305–5313. doi: 10.1128/jvi.65.10.5305-5313.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. D'Agostino D. M., Felber B. K., Harrison J. E., Pavlakis G. N. The Rev protein of human immunodeficiency virus type 1 promotes polysomal association and translation of gag/pol and vpu/env mRNAs. Mol Cell Biol. 1992 Mar;12(3):1375–1386. doi: 10.1128/mcb.12.3.1375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dayton A. I., Terwilliger E. F., Potz J., Kowalski M., Sodroski J. G., Haseltine W. A. Cis-acting sequences responsive to the rev gene product of the human immunodeficiency virus. J Acquir Immune Defic Syndr. 1988;1(5):441–452. [PubMed] [Google Scholar]
  13. Emerman M., Vazeux R., Peden K. The rev gene product of the human immunodeficiency virus affects envelope-specific RNA localization. Cell. 1989 Jun 30;57(7):1155–1165. doi: 10.1016/0092-8674(89)90053-6. [DOI] [PubMed] [Google Scholar]
  14. Fankhauser C., Izaurralde E., Adachi Y., Wingfield P., Laemmli U. K. Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: dissociation by the Rev response element. Mol Cell Biol. 1991 May;11(5):2567–2575. doi: 10.1128/mcb.11.5.2567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Feinberg M. B., Jarrett R. F., Aldovini A., Gallo R. C., Wong-Staal F. HTLV-III expression and production involve complex regulation at the levels of splicing and translation of viral RNA. Cell. 1986 Sep 12;46(6):807–817. doi: 10.1016/0092-8674(86)90062-0. [DOI] [PubMed] [Google Scholar]
  16. Felber B. K., Hadzopoulou-Cladaras M., Cladaras C., Copeland T., Pavlakis G. N. rev protein of human immunodeficiency virus type 1 affects the stability and transport of the viral mRNA. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1495–1499. doi: 10.1073/pnas.86.5.1495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fu X. D., Maniatis T. Factor required for mammalian spliceosome assembly is localized to discrete regions in the nucleus. Nature. 1990 Feb 1;343(6257):437–441. doi: 10.1038/343437a0. [DOI] [PubMed] [Google Scholar]
  18. Green M. R. Biochemical mechanisms of constitutive and regulated pre-mRNA splicing. Annu Rev Cell Biol. 1991;7:559–599. doi: 10.1146/annurev.cb.07.110191.003015. [DOI] [PubMed] [Google Scholar]
  19. Habets W. J., Hoet M. H., De Jong B. A., Van der Kemp A., Van Venrooij W. J. Mapping of B cell epitopes on small nuclear ribonucleoproteins that react with human autoantibodies as well as with experimentally-induced mouse monoclonal antibodies. J Immunol. 1989 Oct 15;143(8):2560–2566. [PubMed] [Google Scholar]
  20. Hammarskjöld M. L., Heimer J., Hammarskjöld B., Sangwan I., Albert L., Rekosh D. Regulation of human immunodeficiency virus env expression by the rev gene product. J Virol. 1989 May;63(5):1959–1966. doi: 10.1128/jvi.63.5.1959-1966.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Huang S., Spector D. L. Nascent pre-mRNA transcripts are associated with nuclear regions enriched in splicing factors. Genes Dev. 1991 Dec;5(12A):2288–2302. doi: 10.1101/gad.5.12a.2288. [DOI] [PubMed] [Google Scholar]
  22. Jiménez-García L. F., Spector D. L. In vivo evidence that transcription and splicing are coordinated by a recruiting mechanism. Cell. 1993 Apr 9;73(1):47–59. doi: 10.1016/0092-8674(93)90159-n. [DOI] [PubMed] [Google Scholar]
  23. Kalland K. H., Langhoff E., Bos H. J., Göttlinger H., Haseltine W. A. Rex-dependent nucleolar accumulation of HTLV-I mRNAs. New Biol. 1991 Apr;3(4):389–397. [PubMed] [Google Scholar]
  24. Kalland K. H., Szilvay A. M., Langhoff E., Haukenes G. Subcellular distribution of human immunodeficiency virus type 1 Rev and colocalization of Rev with RNA splicing factors in a speckled pattern in the nucleoplasm. J Virol. 1994 Mar;68(3):1475–1485. doi: 10.1128/jvi.68.3.1475-1485.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kim S. Y., Byrn R., Groopman J., Baltimore D. Temporal aspects of DNA and RNA synthesis during human immunodeficiency virus infection: evidence for differential gene expression. J Virol. 1989 Sep;63(9):3708–3713. doi: 10.1128/jvi.63.9.3708-3713.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kjems J., Sharp P. A. The basic domain of Rev from human immunodeficiency virus type 1 specifically blocks the entry of U4/U6.U5 small nuclear ribonucleoprotein in spliceosome assembly. J Virol. 1993 Aug;67(8):4769–4776. doi: 10.1128/jvi.67.8.4769-4776.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lerner E. A., Lerner M. R., Janeway C. A., Jr, Steitz J. A. Monoclonal antibodies to nucleic acid-containing cellular constituents: probes for molecular biology and autoimmune disease. Proc Natl Acad Sci U S A. 1981 May;78(5):2737–2741. doi: 10.1073/pnas.78.5.2737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Loewinger L., McKeon F. Mutations in the nuclear lamin proteins resulting in their aberrant assembly in the cytoplasm. EMBO J. 1988 Aug;7(8):2301–2309. doi: 10.1002/j.1460-2075.1988.tb03073.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Maldarelli F., Martin M. A., Strebel K. Identification of posttranscriptionally active inhibitory sequences in human immunodeficiency virus type 1 RNA: novel level of gene regulation. J Virol. 1991 Nov;65(11):5732–5743. doi: 10.1128/jvi.65.11.5732-5743.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Malim M. H., Cullen B. R. Rev and the fate of pre-mRNA in the nucleus: implications for the regulation of RNA processing in eukaryotes. Mol Cell Biol. 1993 Oct;13(10):6180–6189. doi: 10.1128/mcb.13.10.6180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Malim M. H., Hauber J., Fenrick R., Cullen B. R. Immunodeficiency virus rev trans-activator modulates the expression of the viral regulatory genes. Nature. 1988 Sep 8;335(6186):181–183. doi: 10.1038/335181a0. [DOI] [PubMed] [Google Scholar]
  32. Malim M. H., Hauber J., Le S. Y., Maizel J. V., Cullen B. R. The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA. Nature. 1989 Mar 16;338(6212):254–257. doi: 10.1038/338254a0. [DOI] [PubMed] [Google Scholar]
  33. Piñol-Roma S., Dreyfuss G. Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm. Nature. 1992 Feb 20;355(6362):730–732. doi: 10.1038/355730a0. [DOI] [PubMed] [Google Scholar]
  34. Pomerantz R. J., Trono D., Feinberg M. B., Baltimore D. Cells nonproductively infected with HIV-1 exhibit an aberrant pattern of viral RNA expression: a molecular model for latency. Cell. 1990 Jun 29;61(7):1271–1276. doi: 10.1016/0092-8674(90)90691-7. [DOI] [PubMed] [Google Scholar]
  35. Rosbash M., Singer R. H. RNA travel: tracks from DNA to cytoplasm. Cell. 1993 Nov 5;75(3):399–401. doi: 10.1016/0092-8674(93)90373-x. [DOI] [PubMed] [Google Scholar]
  36. Rosen C. A., Pavlakis G. N. Tat and Rev: positive regulators of HIV gene expression. AIDS. 1990 Jun;4(6):499–509. [PubMed] [Google Scholar]
  37. Rosen C. A., Terwilliger E., Dayton A., Sodroski J. G., Haseltine W. A. Intragenic cis-acting art gene-responsive sequences of the human immunodeficiency virus. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2071–2075. doi: 10.1073/pnas.85.7.2071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Ruhl M., Himmelspach M., Bahr G. M., Hammerschmid F., Jaksche H., Wolff B., Aschauer H., Farrington G. K., Probst H., Bevec D. Eukaryotic initiation factor 5A is a cellular target of the human immunodeficiency virus type 1 Rev activation domain mediating trans-activation. J Cell Biol. 1993 Dec;123(6 Pt 1):1309–1320. doi: 10.1083/jcb.123.6.1309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sadaie M. R., Benter T., Wong-Staal F. Site-directed mutagenesis of two trans-regulatory genes (tat-III,trs) of HIV-1. Science. 1988 Feb 19;239(4842):910–913. doi: 10.1126/science.3277284. [DOI] [PubMed] [Google Scholar]
  40. Salahuddin S. Z., Markham P. D., Wong-Staal F., Franchini G., Kalyanaraman V. S., Gallo R. C. Restricted expression of human T-cell leukemia--lymphoma virus (HTLV) in transformed human umbilical cord blood lymphocytes. Virology. 1983 Aug;129(1):51–64. doi: 10.1016/0042-6822(83)90395-1. [DOI] [PubMed] [Google Scholar]
  41. Schwartz S., Felber B. K., Pavlakis G. N. Distinct RNA sequences in the gag region of human immunodeficiency virus type 1 decrease RNA stability and inhibit expression in the absence of Rev protein. J Virol. 1992 Jan;66(1):150–159. doi: 10.1128/jvi.66.1.150-159.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sodroski J., Goh W. C., Rosen C., Dayton A., Terwilliger E., Haseltine W. A second post-transcriptional trans-activator gene required for HTLV-III replication. Nature. 1986 May 22;321(6068):412–417. doi: 10.1038/321412a0. [DOI] [PubMed] [Google Scholar]
  43. Spector D. L. Higher order nuclear organization: three-dimensional distribution of small nuclear ribonucleoprotein particles. Proc Natl Acad Sci U S A. 1990 Jan;87(1):147–151. doi: 10.1073/pnas.87.1.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Szilvay A. M., Nornes S., Haugan I. R., Olsen L., Prasad V. R., Endresen C., Goff S. P., Helland D. E. Epitope mapping of HIV-1 reverse transcriptase with monoclonal antibodies that inhibit polymerase and RNase H activities. J Acquir Immune Defic Syndr. 1992;5(7):647–657. [PubMed] [Google Scholar]
  45. Terwilliger E., Burghoff R., Sia R., Sodroski J., Haseltine W., Rosen C. The art gene product of human immunodeficiency virus is required for replication. J Virol. 1988 Feb;62(2):655–658. doi: 10.1128/jvi.62.2.655-658.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Wang J., Cao L. G., Wang Y. L., Pederson T. Localization of pre-messenger RNA at discrete nuclear sites. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7391–7395. doi: 10.1073/pnas.88.16.7391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Yuan C. C., Kan N., Dunn K. J., Papas T. S., Blair D. G. Properties of a murine retroviral recombinant of avian acute leukemia virus E26: a murine fibroblast assay for v-ets function. J Virol. 1989 Jan;63(1):205–215. doi: 10.1128/jvi.63.1.205-215.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES