Nucleocytoplasmic transport: signals, mechanisms and regulation

In eukaryotic organisms, DNA replication and RNA biogenesis occur in the cell nucleus, whereas protein synthesis occurs in the cytoplasm. Integration of these activities depends on selective transport of proteins and ribonucleoprotein particles between the two compartments. Transport across the nuclear envelope occurs through large multiprotein structures, termed nuclear pore complexes. It is signal-mediated and requires both energy and soluble factors, including shuttling carriers. Here I summarize current understanding of nucleocytoplasmic transport and illustrate the importance of regulated transport for signal transduction.

[1]  G. Blobel,et al.  The GTP-binding protein Ran/TC4 is required for protein import into the nucleus , 1993, Nature.

[2]  G. Blobel,et al.  The two steps of nuclear import, targeting to the nuclear envelope and translocation through the nuclear pore, require different cytosolic factors , 1992, Cell.

[3]  R. Kraft,et al.  Two different subunits of importin cooperate to recognize nuclear localization signals and bind them to the nuclear envelope , 1995, Current Biology.

[4]  U Aebi,et al.  Tpr, a large coiled coil protein whose amino terminus is involved in activation of oncogenic kinases, is localized to the cytoplasmic surface of the nuclear pore complex , 1994, The Journal of cell biology.

[5]  P. Silver,et al.  The NTF2 Gene Encodes an Essential, Highly Conserved Protein That Functions in Nuclear Transport in Vivo* , 1996, The Journal of Biological Chemistry.

[6]  E. Hartmann,et al.  Isolation of a protein that is essential for the first step of nuclear protein import , 1994, Cell.

[7]  I. Kiss,et al.  The overgrown hematopoietic organs-31 tumor suppressor gene of Drosophila encodes an Importin-like protein accumulating in the nucleus at the onset of mitosis , 1995, The Journal of cell biology.

[8]  G. Dreyfuss,et al.  Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm , 1992, Nature.

[9]  C. Dingwall,et al.  RAN/TC4 mutants identify a common requirement for snRNP and protein import into the nucleus , 1996, The Journal of cell biology.

[10]  G. Blobel,et al.  Protein export from the nucleus requires the GTPase Ran and GTP hydrolysis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[11]  D. Thomas,et al.  Inducible nuclear expression of newly synthesized I kappa B alpha negatively regulates DNA-binding and transcriptional activities of NF-kappa B , 1995, Molecular and cellular biology.

[12]  E. Hurt,et al.  Nup145p is required for nuclear export of mRNA and binds homopolymeric RNA in vitro via a novel conserved motif , 1994, Cell.

[13]  G. Blobel,et al.  Purification of a Ran-interacting protein that is required for protein import into the nucleus. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[14]  G. Dreyfuss,et al.  A Novel Receptor-Mediated Nuclear Protein Import Pathway , 1996, Cell.

[15]  M. Emerman,et al.  A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells , 1993, Nature.

[16]  B. Cullen,et al.  Nuclear export of late HIV-1 mRNAs occurs via a cellular protein export pathway. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Zasloff.  tRNA transport from the nucleus in a eukaryotic cell: carrier-mediated translocation process. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[18]  B. Paschal,et al.  Identification of NTF2, a cytosolic factor for nuclear import that interacts with nuclear pore complex protein p62 , 1995, The Journal of cell biology.

[19]  M. Frasch,et al.  Pendulin, a Drosophila protein with cell cycle-dependent nuclear localization, is required for normal cell proliferation , 1995, The Journal of cell biology.

[20]  J. Stȩpiński,et al.  A cap binding protein that may mediate nuclear export of RNA polymerase II-transcribed RNAs , 1992, The Journal of cell biology.

[21]  E. Hurt,et al.  Genetic approaches to nuclear pore structure and function. , 1995, Trends in genetics : TIG.

[22]  T. Pieler,et al.  Protein-mediated nuclear export of RNA: 5S rRNA containing small RNPs in xenopus oocytes , 1990, Cell.

[23]  N. Imamoto,et al.  Loss of RCC1 leads to suppression of nuclear protein import in living cells. , 1994, The Journal of biological chemistry.

[24]  A. Lamond,et al.  The conserved amino‐terminal domain of hSRP1 alpha is essential for nuclear protein import. , 1996, The EMBO journal.

[25]  S. Chen,et al.  A yeast protein that bidirectionally affects nucleocytoplasmic transport. , 1995, Journal of cell science.

[26]  S. Adam,et al.  Cytosolic proteins that specifically bind nuclear location signals are receptors for nuclear import , 1991, Cell.

[27]  M. Stewart,et al.  The 1.6 angstroms resolution crystal structure of nuclear transport factor 2 (NTF2). , 1997, Journal of molecular biology.

[28]  M. Rout,et al.  Isolation of the yeast nuclear pore complex , 1993, The Journal of cell biology.

[29]  R. Lührmann,et al.  In vitro nuclear import of snRNPs: cytosolic factors mediate m3G‐cap dependence of U1 and U2 snRNP transport. , 1994, The EMBO journal.

[30]  M. Terns,et al.  Multiple cis-acting signals for export of pre-U1 snRNA from the nucleus. , 1993, Genes & development.

[31]  R. Laskey,et al.  Nuclear targeting sequences--a consensus? , 1991, Trends in biochemical sciences.

[32]  M. Nomura,et al.  Isolation of a yeast protein kinase that is activated by the protein encoded by SRP1 (Srp1p) and phosphorylates Srp1p complexed with nuclear localization signal peptides. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[33]  S. Adam,et al.  Nuclear protein import in permeabilized mammalian cells requires soluble cytoplasmic factors , 1990, The Journal of cell biology.

[34]  D. Goldfarb,et al.  Facilitated nuclear transport of histone H1 and other small nucleophilic proteins , 1990, Cell.

[35]  D. Goldfarb,et al.  Regulation of RNA processing and transport by a nuclear guanine nucleotide release protein and members of the Ras superfamily. , 1993, The EMBO journal.

[36]  F. Melchior,et al.  Inhibition of nuclear protein import by nonhydrolyzable analogues of GTP and identification of the small GTPase Ran/TC4 as an essential transport factor [published erratum appears in J Cell Biol 1994 Jan;124(1-2):217] , 1993, The Journal of cell biology.

[37]  G. Blobel,et al.  Nup358, a Cytoplasmically Exposed Nucleoporin with Peptide Repeats, Ran-GTP Binding Sites, Zinc Fingers, a Cyclophilin A Homologous Domain, and a Leucine-rich Region (*) , 1995, The Journal of Biological Chemistry.

[38]  C. Feldherr,et al.  EM visualization of nucleocytoplasmic transport processes. , 1990, Electron microscopy reviews.

[39]  A. Lamond,et al.  Identification of hSRP1 alpha as a functional receptor for nuclear localization sequences. , 1995, Science.

[40]  G. Blobel,et al.  Identification of a protein complex that is required for nuclear protein import and mediates docking of import substrate to distinct nucleoporins. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[41]  L. Gerace,et al.  A GTPase distinct from Ran is involved in nuclear protein import , 1996, The Journal of cell biology.

[42]  W. Kabsch,et al.  Crystal structure of the nuclear Ras-related protein Ran in its GDP-bound form , 1995, Nature.

[43]  K. Kalland,et al.  The human immunodeficiency virus type 1 Rev protein shuttles between the cytoplasm and nuclear compartments. , 1994, Molecular and cellular biology.

[44]  U. Aebi,et al.  Sequential Binding of Import Ligands to Distinct Nucleopore Regions During Their Nuclear Import , 1996, Science.

[45]  R. Skaer,et al.  Interpretation of the three-dimensional structure of living nuclei by specimen tilt. , 1975, Journal of cell science.

[46]  P. Grandi,et al.  Functional interaction of Nic96p with a core nucleoporin complex consisting of Nsp1p, Nup49p and a novel protein Nup57p. , 1995, The EMBO journal.

[47]  G. Dreyfuss,et al.  A nuclear export signal in hnRNP A1: A signal-mediated, temperature-dependent nuclear protein export pathway , 1995, Cell.

[48]  M. Aebi,et al.  Nuclear PRP20 protein is required for mRNA export. , 1993, The EMBO journal.

[49]  D. Goldfarb,et al.  Nuclear Export Pathways of tRNA and 40 S Ribosomes Include both Common and Specific Intermediates (*) , 1995, The Journal of Biological Chemistry.

[50]  C. Burd,et al.  hnRNP proteins and the biogenesis of mRNA. , 1993, Annual review of biochemistry.

[51]  A. Lamond,et al.  Characterization of the nuclear protein import mechanism using Ran mutants with altered nucleotide binding specificities. , 1996, The EMBO journal.

[52]  G Rautmann,et al.  Evidence that HIV‐1 Rev directly promotes the nuclear export of unspliced RNA. , 1994, The EMBO journal.

[53]  Joe D. Lewis,et al.  A cap-binding protein complex mediating U snRNA export , 1995, Nature.

[54]  L. Gerace,et al.  Nuclear export signals and the fast track to the cytoplasm , 1995, Cell.

[55]  Tatsuya Seki,et al.  A giant nucleopore protein that binds Ran/TC4 , 1995, Nature.

[56]  M. Rosbash,et al.  Identification of a novel nuclear pore-associated protein as a functional target of the HIV-1 Rev protein in yeast , 1995, Cell.

[57]  M. Powers,et al.  Cytosolic factors in nuclear transport: What's importin? , 1994, Cell.

[58]  M. Radermacher,et al.  Architecture of the Xenopus nuclear pore complex revealed by three- dimensional cryo-electron microscopy , 1993, The Journal of cell biology.

[59]  G. Oster,et al.  What drives the translocation of proteins? , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[60]  W. Boelens,et al.  Nuclear export of different classes of RNA is mediated by specific factors , 1994, The Journal of cell biology.

[61]  G. Blobel,et al.  The peptide repeat domain of nucleoporin Nup98 functions as a docking site in transport across the nuclear pore complex , 1995, Cell.

[62]  G. Blobel,et al.  The human CAN protein, a putative oncogene product associated with myeloid leukemogenesis, is a nuclear pore complex protein that faces the cytoplasm. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[63]  Roger Y Tsien,et al.  Identification of a signal for rapid export of proteins from the nucleus , 1995, Cell.

[64]  P. Silver,et al.  Mutants in a yeast Ran binding protein are defective in nuclear transport. , 1995, The EMBO journal.

[65]  D. Goldfarb,et al.  Multiple pathways in nuclear transport: the import of U2 snRNP occurs by a novel kinetic pathway , 1991, The Journal of cell biology.

[66]  T. Hunter,et al.  Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus , 1995, Current Biology.

[67]  F. Buss,et al.  Macromolecular interactions in the nucleoporin p62 complex of rat nuclear pores: binding of nucleoporin p54 to the rod domain of p62 , 1995, The Journal of cell biology.

[68]  D. Newmeyer,et al.  In vitro transport of a fluorescent nuclear protein and exclusion of non-nuclear proteins , 1986, The Journal of cell biology.

[69]  B. Daneholt,et al.  A nuclear cap-binding complex binds Balbiani ring pre-mRNA cotranscriptionally and accompanies the ribonucleoprotein particle during nuclear export , 1996, The Journal of cell biology.

[70]  G. Dreyfuss,et al.  A nuclear localization domain in the hnRNP A1 protein , 1995, The Journal of cell biology.

[71]  C. Cole,et al.  Isolation and characterization of RAT1: an essential gene of Saccharomyces cerevisiae required for the efficient nucleocytoplasmic trafficking of mRNA. , 1992, Genes & development.

[72]  S. Adam,et al.  Sequence and characterization of cytoplasmic nuclear protein import factor p97 , 1995, The Journal of cell biology.

[73]  M. Malim,et al.  The HIV-1 Rev trans-activator shuttles between the nucleus and the cytoplasm. , 1994, Genes & development.

[74]  C. Feldherr,et al.  Role of nuclear trafficking in regulating cellular activity. , 1994, International review of cytology.

[75]  P. D’Eustachio,et al.  Characterization of proteins that interact with the cell-cycle regulatory protein Ran/TC4 , 1993, Nature.

[76]  I. Macara,et al.  Ran Binding Domains Promote the Interaction of Ran with p97/β-Karyopherin, Linking the Docking and Translocation Steps of Nuclear Import (*) , 1996, The Journal of Biological Chemistry.

[77]  Michael R. Green,et al.  HIV Rev uses a conserved cellular protein export pathway for the nucleocytoplasmic transport of viral RNAs , 1996, Current Biology.

[78]  S. Riva,et al.  Nucleo-cytoplasmic distribution of human hnRNP proteins: a search for the targeting domains in hnRNP A1. , 1995, Journal of cell science.

[79]  G. Blobel,et al.  A nuclear pore complex protein that contains zinc finger motifs, binds DNA, and faces the nucleoplasm , 1993, Cell.

[80]  X. Hua,et al.  SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis , 1994, Cell.

[81]  L. Kühn,et al.  Nuclear export of proteins: The role of nuclear retention , 1993, Cell.

[82]  U. Aebi,et al.  The nuclear pore complex , 1993, The Journal of cell biology.

[83]  P. Baeuerle,et al.  Function and activation of NF-kappa B in the immune system. , 1994, Annual review of immunology.

[84]  R. Kraft,et al.  Importin Provides a Link between Nuclear Protein Import and U snRNA Export , 1996, Cell.

[85]  P. Silver,et al.  Dynamic localization of the nuclear import receptor and its interactions with transport factors , 1996, The Journal of cell biology.

[86]  E. Kiseleva,et al.  A Pre-mRNA-Binding Protein Accompanies the RNA from the Gene through the Nuclear Pores and into Polysomes , 1996, Cell.

[87]  P. Silver,et al.  A protein that shuttles between the nucleus and the cytoplasm is an important mediator of RNA export. , 1996, Genes & development.

[88]  Uttam Surana,et al.  The role of phosphorylation and the CDC28 protein kinase in cell cycle-regulated nuclear import of the S. cerevisiae transcription factor SW15 , 1991, Cell.

[89]  Ronald A. Milligan,et al.  Architecture and design of the nuclear pore complex , 1992, Cell.

[90]  R. Schneiter,et al.  Isolation and characterization of Saccharomyces cerevisiae mRNA transport-defective (mtr) mutants , 1994 .

[91]  E. Hartmann,et al.  Distinct functions for the two importin subunits in nuclear protein import , 1995, Nature.

[92]  F. Bischoff,et al.  Identification of different roles for RanGDP and RanGTP in nuclear protein import. , 1996, The EMBO journal.

[93]  G. Blobel,et al.  Mammalian karyopherin alpha 1 beta and alpha 2 beta heterodimers: alpha 1 or alpha 2 subunit binds nuclear localization signal and beta subunit interacts with peptide repeat-containing nucleoporins. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[94]  M. Goldberg,et al.  Structural and functional organization of the nuclear envelope. , 1995, Current opinion in cell biology.

[95]  R. Laskey,et al.  Comparative mutagenesis of nuclear localization signals reveals the importance of neutral and acidic amino acids , 1996, Current Biology.

[96]  P. Silver,et al.  Rna1p, a Ran/TC4 GTPase activating protein, is required for nuclear import , 1995, The Journal of cell biology.

[97]  A. Hopper,et al.  Regulation of mRNA export in response to stress in Saccharomyces cerevisiae. , 1996, Genes & development.

[98]  C. Lehner,et al.  Major nucleolar proteins shuttle between nucleus and cytoplasm , 1989, Cell.

[99]  G. Blobel,et al.  Role of the Nuclear Transport Factor p10 in Nuclear Import , 1996, Science.

[100]  N. Imamoto,et al.  In vivo evidence for involvement of a 58 kDa component of nuclear pore‐targeting complex in nuclear protein import. , 1995, The EMBO journal.

[101]  S. Wente,et al.  An RNA-export mediator with an essential nuclear export signal , 1996, Nature.

[102]  F. Bischoff,et al.  Co‐activation of RanGTPase and inhibition of GTP dissociation by Ran‐GTP binding protein RanBP1. , 1995, The EMBO journal.

[103]  U. Aebi,et al.  Exploring nuclear pore complex structure and function in molecular detail , 1995, Journal of Cell Science.

[104]  E. Lund,et al.  Diverse effects of the guanine nucleotide exchange factor RCC1 on RNA transport. , 1995, Science.

[105]  L. Davis,et al.  The nuclear pore complex. , 1995, Annual review of biochemistry.

[106]  G. Blobel,et al.  Kap104p: A Karyopherin Involved in the Nuclear Transport of Messenger RNA Binding Proteins , 1996, Science.

[107]  Helen M. Kent,et al.  The 1.6 Å Resolution Crystal Structure of Nuclear Transport Factor 2 (NTF2) , 1996 .

[108]  C. Delphin,et al.  Nucleotide-specific interaction of Ran/TC4 with nuclear transport factors NTF2 and p97. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[109]  G. Blobel,et al.  Nuclear protein import: Ran-GTP dissociates the karyopherin alphabeta heterodimer by displacing alpha from an overlapping binding site on beta. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[110]  J. L. Watkins,et al.  The GLFG repetitive region of the nucleoporin Nup116p interacts with Kap95p, an essential yeast nuclear import factor , 1995, The Journal of cell biology.

[111]  B. Cullen,et al.  Identification of a novel cellular cofactor for the Rev/Rex class of retroviral regulatory proteins , 1995, Cell.

[112]  N. Imamoto,et al.  A Karyophilic Protein Forms a Stable Complex with Cytoplasmic Components Prior to Nuclear Pore Binding (*) , 1995, The Journal of Biological Chemistry.

[113]  Utz Fischer,et al.  The HIV-1 Rev Activation Domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs , 1995, Cell.

[114]  L. Gerace,et al.  Molecular and functional characterization of the p62 complex, an assembly of nuclear pore complex glycoproteins , 1996, The Journal of cell biology.

[115]  S. Adam,et al.  RanBP1 stabilizes the interaction of Ran with p97 nuclear protein import , 1996, The Journal of cell biology.

[116]  M. Malim,et al.  Amphibian transcription factor IIIA proteins contain a sequence element functionally equivalent to the nuclear export signal of human immunodeficiency virus type 1 Rev. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[117]  U. Aebi,et al.  Interactions and three-dimensional localization of a group of nuclear pore complex proteins , 1994, The Journal of cell biology.

[118]  B. Séraphin,et al.  A family of Ran binding proteins that includes nucleoporins. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[119]  E. Milgrom,et al.  Nucleocytoplasmic shuttling of the progesterone receptor. , 1991, The EMBO journal.

[120]  U. Aebi,et al.  Toward the molecular details of the nuclear pore complex. , 1994, Journal of structural biology.

[121]  E. Hartmann,et al.  A 41 amino acid motif in importin‐alpha confers binding to importin‐beta and hence transit into the nucleus. , 1996, The EMBO journal.

[122]  G. Blobel,et al.  Protein import into nuclei: association and dissociation reactions involving transport substrate, transport factors, and nucleoporins , 1995, Cell.

[123]  P. Silver,et al.  A GTPase Controlling Nuclear Trafficking: Running the Right Way or Walking RANdomly? , 1996, Cell.

[124]  P. Grandi,et al.  A novel nuclear pore protein Nup82p which specifically binds to a fraction of Nsp1p , 1995, The Journal of cell biology.

[125]  F. Melchior,et al.  GTP hydrolysis by Ran occurs at the nuclear pore complex in an early step of protein import , 1995, The Journal of cell biology.

[126]  Keisuke Toyama,et al.  The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP96 and class I homeoprotein HOXA9 , 1996, Nature Genetics.

[127]  M. Rosbash,et al.  A role for nucleoporin FG repeat domains in export of human immunodeficiency virus type 1 Rev protein and RNA from the nucleus , 1996, Molecular and cellular biology.

[128]  Michael R. Green,et al.  A human nucleoporin-like protein that specifically interacts with HIV Rev , 1995, Nature.

[129]  B. Cullen,et al.  Protein sequence requirements for function of the human T-cell leukemia virus type 1 Rex nuclear export signal delineated by a novel in vivo randomization-selection assay , 1996, Molecular and cellular biology.

[130]  B. Burke,et al.  Nuclear pore complex proteins. , 1995, International review of cytology.

[131]  E. Nigg.  Mechanisms of signal transduction to the cell nucleus. , 1990, Advances in cancer research.

[132]  B. Daneholt,et al.  Structural interaction between the nuclear pore complex and a specific translocating RNP particle , 1995, The Journal of cell biology.

[133]  G. Blobel,et al.  Identification of a Yeast Karyopherin Heterodimer That Targets Import Substrate to Mammalian Nuclear Pore Complexes (*) , 1995, The Journal of Biological Chemistry.

[134]  R. Laskey,et al.  A polypeptide domain that specifies migration of nucleoplasmin into the nucleus , 1982, Cell.

[135]  H. Fried,et al.  Cytoplasmic transport of ribosomal subunits microinjected into the Xenopus laevis oocyte nucleus: a generalized, facilitated process , 1990, The Journal of cell biology.

[136]  U. Aebi,et al.  Toward the molecular dissection of protein import into nuclei. , 1996, Current opinion in cell biology.