Skip to main content
PMC home page
The Journal of Cell Biology logoLink to The Journal of Cell Biology
. 1996 Sep 2;134(6):1365–1373. doi: 10.1083/jcb.134.6.1365

The hnRNP C proteins contain a nuclear retention sequence that can override nuclear export signals

PMCID: PMC2121000  PMID: 8830767

Abstract

Nascent pre-mRNAs associate with the abundant heterogeneous nuclear RNP (hnRNP) proteins and remain associated with them throughout the time they are in the nucleus. The hnRNP proteins can be divided into two groups according to their nucleocytoplasmic transport properties. One group is completely restricted to the nucleus in interphase cells, whereas the other group, although primarily nuclear at steady state, shuttles between the nucleus and the cytoplasm. Nuclear export of the shuttling hnRNP proteins is mediated by nuclear export signals (NESs). Mounting evidence indicates that NES-bearing hnRNP proteins are mediators of mRNA export. The hnRNP C proteins are representative of the nonshuttling group of hnRNP proteins. Here we show that hnRNP C proteins are restricted to the nucleus not because they lack an NES, but because they bear a nuclear retention sequence (NRS) that is capable of overriding NESs. The NRS comprises approximately 78 amino acids and is largely within the auxiliary domain of hnRNP C1. We suggest that the removal of NRS-containing hnRNP proteins from pre- mRNA/mRNA is required for mRNA export from the nucleus and is an essential step in the pathway of gene expression.

Full Text

The Full Text of this article is available as a PDF (2.2 MB).

Selected References

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

  1. Boulikas T. Nuclear localization signals (NLS). Crit Rev Eukaryot Gene Expr. 1993;3(3):193–227. [PubMed] [Google Scholar]
  2. Burd C. G., Dreyfuss G. Conserved structures and diversity of functions of RNA-binding proteins. Science. 1994 Jul 29;265(5172):615–621. doi: 10.1126/science.8036511. [DOI] [PubMed] [Google Scholar]
  3. Burd C. G., Swanson M. S., Görlach M., Dreyfuss G. Primary structures of the heterogeneous nuclear ribonucleoprotein A2, B1, and C2 proteins: a diversity of RNA binding proteins is generated by small peptide inserts. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9788–9792. doi: 10.1073/pnas.86.24.9788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Buvoli M., Cobianchi F., Bestagno M. G., Mangiarotti A., Bassi M. T., Biamonti G., Riva S. Alternative splicing in the human gene for the core protein A1 generates another hnRNP protein. EMBO J. 1990 Apr;9(4):1229–1235. doi: 10.1002/j.1460-2075.1990.tb08230.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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]
  6. Choi Y. D., Grabowski P. J., Sharp P. A., Dreyfuss G. Heterogeneous nuclear ribonucleoproteins: role in RNA splicing. Science. 1986 Mar 28;231(4745):1534–1539. doi: 10.1126/science.3952495. [DOI] [PubMed] [Google Scholar]
  7. Cuomo C. A., Kirch S. A., Gyuris J., Brent R., Oettinger M. A. Rch1, a protein that specifically interacts with the RAG-1 recombination-activating protein. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6156–6160. doi: 10.1073/pnas.91.13.6156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cáceres J. F., Stamm S., Helfman D. M., Krainer A. R. Regulation of alternative splicing in vivo by overexpression of antagonistic splicing factors. Science. 1994 Sep 16;265(5179):1706–1709. doi: 10.1126/science.8085156. [DOI] [PubMed] [Google Scholar]
  9. Dingwall C., Laskey R. A. Nuclear targeting sequences--a consensus? Trends Biochem Sci. 1991 Dec;16(12):478–481. doi: 10.1016/0968-0004(91)90184-w. [DOI] [PubMed] [Google Scholar]
  10. Dreyfuss G., Matunis M. J., Piñol-Roma S., Burd C. G. hnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem. 1993;62:289–321. doi: 10.1146/annurev.bi.62.070193.001445. [DOI] [PubMed] [Google Scholar]
  11. Evan G. I., Lewis G. K., Ramsay G., Bishop J. M. Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product. Mol Cell Biol. 1985 Dec;5(12):3610–3616. doi: 10.1128/mcb.5.12.3610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Görlach M., Burd C. G., Dreyfuss G. The determinants of RNA-binding specificity of the heterogeneous nuclear ribonucleoprotein C proteins. J Biol Chem. 1994 Sep 16;269(37):23074–23078. [PubMed] [Google Scholar]
  13. Görlich D., Mattaj I. W. Nucleocytoplasmic transport. Science. 1996 Mar 15;271(5255):1513–1518. doi: 10.1126/science.271.5255.1513. [DOI] [PubMed] [Google Scholar]
  14. Hamm J., Mattaj I. W. Monomethylated cap structures facilitate RNA export from the nucleus. Cell. 1990 Oct 5;63(1):109–118. doi: 10.1016/0092-8674(90)90292-m. [DOI] [PubMed] [Google Scholar]
  15. Holcomb E. R., Friedman D. L. Phosphorylation of the C-proteins of HeLa cell hnRNP particles. Involvement of a casein kinase II-type enzyme. J Biol Chem. 1984 Jan 10;259(1):31–40. [PubMed] [Google Scholar]
  16. Horton R. M., Cai Z. L., Ho S. N., Pease L. R. Gene splicing by overlap extension: tailor-made genes using the polymerase chain reaction. Biotechniques. 1990 May;8(5):528–535. [PubMed] [Google Scholar]
  17. Izaurralde E., Mattaj I. W. RNA export. Cell. 1995 Apr 21;81(2):153–159. doi: 10.1016/0092-8674(95)90323-2. [DOI] [PubMed] [Google Scholar]
  18. Laskey R. A., Dingwall C. Nuclear shuttling: the default pathway for nuclear proteins? Cell. 1993 Aug 27;74(4):585–586. doi: 10.1016/0092-8674(93)90505-k. [DOI] [PubMed] [Google Scholar]
  19. Legrain P., Rosbash M. Some cis- and trans-acting mutants for splicing target pre-mRNA to the cytoplasm. Cell. 1989 May 19;57(4):573–583. doi: 10.1016/0092-8674(89)90127-x. [DOI] [PubMed] [Google Scholar]
  20. Matunis M. J., Michael W. M., Dreyfuss G. Characterization and primary structure of the poly(C)-binding heterogeneous nuclear ribonucleoprotein complex K protein. Mol Cell Biol. 1992 Jan;12(1):164–171. doi: 10.1128/mcb.12.1.164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mayeda A., Krainer A. R. Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2. Cell. 1992 Jan 24;68(2):365–375. doi: 10.1016/0092-8674(92)90477-t. [DOI] [PubMed] [Google Scholar]
  22. Mayrand S. H., Dwen P., Pederson T. Serine/threonine phosphorylation regulates binding of C hnRNP proteins to pre-mRNA. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7764–7768. doi: 10.1073/pnas.90.16.7764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mehlin H., Daneholt B. The Balbiani ring particle: a model for the assembly and export of RNPs from the nucleus? Trends Cell Biol. 1993 Dec;3(12):443–447. doi: 10.1016/0962-8924(93)90034-x. [DOI] [PubMed] [Google Scholar]
  24. Michael W. M., Choi M., Dreyfuss G. A nuclear export signal in hnRNP A1: a signal-mediated, temperature-dependent nuclear protein export pathway. Cell. 1995 Nov 3;83(3):415–422. doi: 10.1016/0092-8674(95)90119-1. [DOI] [PubMed] [Google Scholar]
  25. Michaud E. J., Bultman S. J., Stubbs L. J., Woychik R. P. The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of a novel RNA-binding protein. Genes Dev. 1993 Jul;7(7A):1203–1213. doi: 10.1101/gad.7.7a.1203. [DOI] [PubMed] [Google Scholar]
  26. Munroe S. H., Dong X. F. Heterogeneous nuclear ribonucleoprotein A1 catalyzes RNA.RNA annealing. Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):895–899. doi: 10.1073/pnas.89.3.895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Olsen H. S., Cochrane A. W., Rosen C. Interaction of cellular factors with intragenic cis-acting repressive sequences within the HIV genome. Virology. 1992 Dec;191(2):709–715. doi: 10.1016/0042-6822(92)90246-l. [DOI] [PubMed] [Google Scholar]
  28. Piñol-Roma S., Dreyfuss G. Cell cycle-regulated phosphorylation of the pre-mRNA-binding (heterogeneous nuclear ribonucleoprotein) C proteins. Mol Cell Biol. 1993 Sep;13(9):5762–5770. doi: 10.1128/mcb.13.9.5762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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]
  30. Piñol-Roma S., Dreyfuss G. hnRNP proteins: localization and transport between the nucleus and the cytoplasm. Trends Cell Biol. 1993 May;3(5):151–155. doi: 10.1016/0962-8924(93)90135-n. [DOI] [PubMed] [Google Scholar]
  31. Portman D. S., Dreyfuss G. RNA annealing activities in HeLa nuclei. EMBO J. 1994 Jan 1;13(1):213–221. doi: 10.1002/j.1460-2075.1994.tb06251.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Schmidt-Zachmann M. S., Dargemont C., Kühn L. C., Nigg E. A. Nuclear export of proteins: the role of nuclear retention. Cell. 1993 Aug 13;74(3):493–504. doi: 10.1016/0092-8674(93)80051-f. [DOI] [PubMed] [Google Scholar]
  33. Simons F. H., Broers F. J., Van Venrooij W. J., Pruijn G. J. Characterization of cis-acting signals for nuclear import and retention of the La (SS-B) autoantigen. Exp Cell Res. 1996 May 1;224(2):224–236. doi: 10.1006/excr.1996.0132. [DOI] [PubMed] [Google Scholar]
  34. Siomi H., Dreyfuss G. A nuclear localization domain in the hnRNP A1 protein. J Cell Biol. 1995 May;129(3):551–560. doi: 10.1083/jcb.129.3.551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Swanson M. S., Nakagawa T. Y., LeVan K., Dreyfuss G. Primary structure of human nuclear ribonucleoprotein particle C proteins: conservation of sequence and domain structures in heterogeneous nuclear RNA, mRNA, and pre-rRNA-binding proteins. Mol Cell Biol. 1987 May;7(5):1731–1739. doi: 10.1128/mcb.7.5.1731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sweet D. J., Gerace L. Taking from the cytoplasm and giving to the pore: soluble transport factors in nuclear protein import. Trends Cell Biol. 1995 Dec;5(12):444–447. doi: 10.1016/s0962-8924(00)89108-4. [DOI] [PubMed] [Google Scholar]
  37. Vaughan J. H., Valbracht J. R., Nguyen M. D., Handley H. H., Smith R. S., Patrick K., Rhodes G. H. Epstein-Barr virus-induced autoimmune responses. I. Immunoglobulin M autoantibodies to proteins mimicking and not mimicking Epstein-Barr virus nuclear antigen-1. J Clin Invest. 1995 Mar;95(3):1306–1315. doi: 10.1172/JCI117781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Visa N., Alzhanova-Ericsson A. T., Sun X., Kiseleva E., Björkroth B., Wurtz T., Daneholt B. A pre-mRNA-binding protein accompanies the RNA from the gene through the nuclear pores and into polysomes. Cell. 1996 Jan 26;84(2):253–264. doi: 10.1016/s0092-8674(00)80980-0. [DOI] [PubMed] [Google Scholar]
  39. Yang X., Bani M. R., Lu S. J., Rowan S., Ben-David Y., Chabot B. The A1 and A1B proteins of heterogeneous nuclear ribonucleoparticles modulate 5' splice site selection in vivo. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6924–6928. doi: 10.1073/pnas.91.15.6924. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

RESOURCES