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Results for “Nuclear Localization Signals”

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PubMed2001

Nucleocytoplasmic shuttling by human immunodeficiency virus type 1 Vpr.

Human immunodeficiency virus type 1 (HIV-1) is capable of infecting nondividing cells such as macrophages because the viral preintegration complex is able to actively traverse the limiting nuclear pore due to the redundant and possibly overlapping nuclear import signals present in Vpr, matrix, and integrase. We have previously recognized the presence of at least two distinct and novel nuclear import signals residing within Vpr that, unlike matrix and integrase, bypass the classical importin alpha/beta-dependent signals and do not require energy or a RanGTP gradient. We now report that the carboxy-terminal region of Vpr (amino acids 73 to 96) contains a bipartite nuclear localization signal (NLS) composed of multiple arginine residues. Surprisingly, when the leucine-rich Vpr(1-71) fragment, previously shown to harbor an NLS, or full-length Vpr is fused to the C terminus of a green fluorescent protein-pyruvate kinase (GFP-PK) chimera, the resultant protein is almost exclusively detected in the cytoplasm. However, the addition of leptomycin B (LMB), a potent inhibitor of CRM1-dependent nuclear export, produces a shift from a cytoplasmic localization to a nuclear pattern, suggesting that these Vpr fusion proteins shuttle into and out of the nucleus. Studies of nuclear import with GFP-PK-Vpr fusion proteins in the presence of LMB reveals that both of the leucine-rich alpha-helices are required for effective nuclear uptake and thus define a unique NLS. Using a modified heterokaryon analysis, we have localized the Vpr nuclear export signal to the second leucine-rich helix, overlapping a portion of the amino-terminal nuclear import signal. These studies thus define HIV-1 Vpr as a nucleocytoplasmic shuttling protein.

Amino Acid Sequence↗

PubMed1997

Sequence determinants for hnRNP I protein nuclear localization.

hnRNP I, also referred to as polypyrimidine tract binding protein, is one of the proteins associated with nascent pre-mRNA in the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes. As for all karyophilic proteins, the nuclear import of hnRNP proteins requires specific sequence determinants that in many instances differ from the canonical import signal. In order to identify the sequences responsible for the nuclear localization, various hnRNP I portions were fused to a reporter protein (bacterial chloramphenicol acetyl transferase) and used in transient transfection assay. By this approach we identified a 60-amino-acid sequence located at the amino terminus of hnRNP I (designated NLD-I) that is both necessary and sufficient for nuclear localization. NLD-I represents a novel bipartite type of nuclear localization signal that bears no resemblance to other nuclear localization determinants so far identified in hnRNP proteins.

3T3 Cells↗

PubMed2005

Nuclear import of the histone acetyltransferase complex SAS-I in Saccharomyces cerevisiae.

The protein complex SAS-I links histone acetylation to the assembly of repressed chromatin in Saccharomyces cerevisiae. Sas2p, the histone acetyltransferase subunit of SAS-I, forms a complex with Sas4p and Sas5p, which are both required for maximal complex activity. In this study, we found that Sas4p was the central subunit of the SAS-I complex, bridging Sas2p and Sas5p. We demonstrated that the nuclear import of Sas2p and Sas5p was mediated by two karyopherins/importins, Kap123p and Pse1p, and both were associated in vivo with these importins. By contrast, Sas4p was not a substrate of Kap123p or Pse1p, suggesting that the nuclear import of the SAS-I subunits occurred independently of each other. Several other non-essential karyopherins were not involved in the nuclear import of SAS-I subunits. When the putative nuclear localization signal (NLS) of Sas2p was deleted, nuclear accumulation of Sas2p was significantly decreased. By contrast, deletion of the proposed NLS of Sas4p had no influence on its nuclear localization. An unknown signal region was located in the N-terminal domain of Sas5p and was responsible for the nuclear import by Kap123p and Pse1p. We found a striking similarity between the NLS sequences of Sas2p and those of histones H3 and H4, which were recently reported to be further import substrates of Kap123p and Pse1p. A database search based on the aligned consensus sequence revealed potential new import substrates of the Kap123p and Pse1p nuclear import pathways, which are connected to chromatin function.

Acetyltransferases↗

PubMed1996

Assessment of glucocorticoid receptor-heat shock protein 90 interactions in vivo during nucleocytoplasmic trafficking.

Unliganded glucocorticoid receptors (GRs) that reside in the cytoplasm exist as heteromeric complexes comprised minimally of 90-kDa heat shock protein (hsp90) hsp70 and p56, a 56-kDa immunophilin. The binding of hsp90 to the GR occurs primarily through its carboxy-terminal, ligand-binding domain. Dissociation of GR-associated proteins accompanies hormone binding and leads to the exposure of its various functional domains. Although an association with hsp90 presumably masks the GR nuclear localization signal sequence, the recent demonstration of the coimport of GR and hsp90 into nuclei has led to the hypothesis that hsp90 facilitates GR interactions with the nuclear transport machinery. In this report we examined whether the dynamics of GR/hsp90 interactions in vivo influences its trafficking both into and out of the nucleus. GR/hsp90 complexes were stabilized in vivo by the introduction of sodium molybdate to cultured cells using a liposome-mediated delivery system. In agreement with previous in vitro studies, we found that stabilization of GR/hsp90 complexes in live cells severely restricts hormone-dependent nuclear import of GR. Constitutive nuclear import of a GR deletion derivative that does not bind hsp90 is unaffected by intracellular administration of molybdate, demonstrating that the inhibitory effects of molybdate require the coupling of the nuclear localization signal sequence to the GR ligand-binding domain. Interestingly, molybdate treatment traps both GR and progesterone receptor in the cytoplasm of cells chronically exposed to hormone, indicating that shuttling GRs and progesterone receptors can export, but not reimport into nuclei in the presence of molybdate. This result implies that the reassociation of recycled receptors with hsp90 must be an obligatory step for receptors that exit the nucleus to reacquire the capacity for nuclear import.

Animals↗

PubMed2001

Design and in vitro characterization of a single regulatory module for efficient control of gene expression in both plasmid DNA and a self-inactivating lentiviral vector.

BACKGROUND: Regulation of transgene expression in target cells represents a critical and challenging aspect of gene therapy. Recently, a two-plasmid tetracycline-inducible system was developed in which the tetracycline repressor (tetR) alone, rather than the tetR-VP16 fusion derivative, was shown to function as a potent trans-modulator of a second plasmid that contains two tandem repeats of the tetracycline operator (tetO) inserted between the TATA box and the transcription start site of the hCMV major immediate-early promoter. A technological advance in this area would be the development of a single autoregulatory cassette that incorporates both of these components into nonviral and viral gene transfer vectors. For the latter, an inducible lentiviral vector that is capable of temporal and quantitative control of gene expression in either dividing or nondividing cells is highly desirable. MATERIALS AND METHODS: A one-piece inducible (1Pi) autoregulatory cassette was constructed to provide IRES-mediated translation of the tetR as well as tight control over the tetO unit preventing transcription initiation of the first cistron in the absence of the tetracycline. To increase efficiency of tetR-mediated repression, a nuclear localization signal was incorporated at the 3' end of the tetR gene. Regulation of gene expression at the transcriptional and protein level was analyzed in transient transfection experiments using plasmid DNA. Construction of a self-inactivating lentiviral vector containing this 1Pi cassette allowed the study of its long-term effectiveness in primary human cells. RESULTS: The 1Pi autoregulatory cassette when incorporated into plasmid DNA allows efficient control of the secretable hEGF as well as eGFP expression in a variety of cell types. Transient transfection studies demonstrated that the time course of repression is different for the 1Pi and two-plasmid system (2Pi). In the 2Pi system, greater repression is seen with the first 24-48 hr; however, by 72 hr, similar levels of repression with the 1Pi and 2Pi systems are obtained. This regulation is reached three times faster when the tetR is modified with a nuclear localization signal to direct nascent proteins into the nuclear compartment. In addition, stable transduction of human umbilical vein endothelial cells (HUVEC) with a self-inactivating lentiviral vector incorporating this single regulator cassette provided tetracycline-inducible control of gene expression that is not diminished over time and is completely reversible upon removal of tetracycline. CONCLUSIONS: These results suggest a model in which the 1Pi autoregulatory system reaches a steady state over time, the minimal amount of tetR produced by the basal activity of the CMV promoter and accumulated is adequate to replace the tetR that is lost over time. These studies also show that the inducible self-inactivating lentiviral vector can temporally and reversibly regulate transgene expression in HUVECs. The use of this transcriptional control unit in both nonviral and viral vector delivery systems will constitute an attractive technological advance for many gene therapy applications where temporal and quantitative control of gene expression is desired. The strengths and limitations of the 1Pi system are discussed.

Animals↗

PubMed2005

Nup50/Npap60 function in nuclear protein import complex disassembly and importin recycling.

Nuclear import of proteins containing classical nuclear localization signals (NLS) is mediated by the importin-alpha:beta complex that binds cargo in the cytoplasm and facilitates its passage through nuclear pores, after which nuclear RanGTP dissociates the import complex and the importins are recycled. In vertebrates, import is stimulated by nucleoporin Nup50, which has been proposed to accompany the import complex through nuclear pores. However, we show here that the Nup50 N-terminal domain actively displaces NLSs from importin-alpha, which would be more consistent with Nup50 functioning to coordinate import complex disassembly and importin recycling. The crystal structure of the importin-alpha:Nup50 complex shows that Nup50 binds at two sites on importin-alpha. One site overlaps the secondary NLS-binding site, whereas the second extends along the importin-alpha C-terminus. Mutagenesis indicates that interaction at both sites is required for Nup50 to displace NLSs. The Cse1p:Kap60p:RanGTP complex structure suggests how Nup50 is then displaced on formation of the importin-alpha export complex. These results provide a rationale for understanding the series of interactions that orchestrate the terminal steps of nuclear protein import.

Amino Acid Sequence↗

PubMed1998

Disruption of PML-associated nuclear bodies mediated by the human cytomegalovirus major immediate early gene product.

The PML gene product is associated with a defined nuclear structure (10-20 per cell) known variously as PML-bodies, ND10, PODs or Kr bodies. Certain conditions are known to compromise the integrity of PML-bodies; these include environmental stress (e.g. heat shock), a chromosomal translocation-associated acute promyelocytic leukaemia, and infection with certain viruses [including human cytomegalovirus (HCMV), herpes simplex virus type 1 and adenovirus]. Expression of the HCMV major immediate early (IE) protein (IE1(491aa)) is by itself sufficient to cause disruption of PML-bodies, resulting in the dispersal of the PML antigen uniformly throughout the nucleus. In uninfected cells undergoing mitosis PML is excluded from chromatin. However, both IE1(491aa) and PML were observed to associate with mitotic chromosomes in cells infected with HCMV or transfected with the IE1 gene. A series of in-frame IE1 deletion mutants was used in DNA transfection experiments to identify two large sequence elements (aa 132-274 and the C-terminal aa 347-491) not required for dispersal of the PML antigen. However, a putative leucine-zipper domain (aa 105-139), a putative zinc-finger domain (aa 267-286) and exon 2 and 3 coding sequences (aa 6-85) were required. The association of the IE1 gene product with chromatin required an acidic domain near the C terminus (aa 421-486). The interaction of IE1(491aa) with chromatin was therefore not required for the disruption of PML-bodies. Exon 2 (aa 1-24) was shown to encode a nuclear localization signal.

Animals↗

PubMed1998

Cse1p is involved in export of yeast importin alpha from the nucleus.

Proteins bearing a nuclear localization signal (NLS) are targeted to the nucleus by the heterodimeric transporter importin. Importin alpha binds to the NLS and to importin beta, which carries it through the nuclear pore complex (NPC). Importin disassembles in the nucleus, evidently by binding of RanGTP to importin beta. The importin subunits are exported separately. We investigated the role of Cse1p, the Saccharomyces cerevisiae homologue of human CAS, in nuclear export of Srp1p (yeast importin alpha). Cse1p is located predominantly in the nucleus but also is present in the cytoplasm and at the NPC. We analyzed the in vivo localization of the importin subunits fused to the green fluorescent protein in wild-type and cse1-1 mutant cells. Srp1p but not importin beta accumulated in nuclei of cse1-1 mutants, which are defective in NLS import but not defective in NLS-independent import pathways. Purified Cse1p binds with high affinity to Srp1p only in the presence of RanGTP. The complex is dissociated by the cytoplasmic RanGTP-binding protein Yrb1p. Combined with the in vivo results, this suggests that a complex containing Srp1p, Cse1p, and RanGTP is exported from the nucleus and is subsequently disassembled in the cytoplasm by Yrb1p. The formation of the trimeric Srp1p-Cse1p-RanGTP complex is inhibited by NLS peptides, indicating that only NLS-free Srp1p will be exported to the cytoplasm.

Carrier Proteins↗

PubMed2004

Nuclear import and activity of histone deacetylase in Xenopus oocytes is regulated by phosphorylation.

Most of the histone deacetylase (HDAC) activity detected in oocytes and early embryos of Xenopus can be accounted for by the presence of a protein complex that contains the maternal HDACm protein. This complex appears to fulfil the conditions required of a 'deposition' histone deacetylase, its primary function being to deacetylate the core histones incorporated into newly-synthesized chromatin during the rapid cell cycles leading up to blastula. A major event in the assembly and accumulation of the HDAC complex is the translocation of the HDACm protein into the germinal vesicle during oogenesis. Here we examine the features of HDACm that are responsible for its nuclear uptake and enzyme activity, identifying the charged C-terminal domain as a target for modification by phosphorylation. Whereas, one phosphorylation site lying within the putative nuclear localization signal, T445, is required for efficient nuclear import of a GST-carboxy-tail fusion, two others, S421 and S423, appear to effect release from the import receptors. Although overexpression of recombinant HDACm in oocytes leads to premature condensation of endogenous chromatin, this effect is abrogated in vivo by mutation of S421A and S423A. Thus, both translocation and activity of HDACm appear to be regulated by specific phosphorylation events. These results have implications for techniques involving the transfer of somatic nuclei into enucleated oocytes.

Active Transport, Cell Nucleus↗

PubMed2006

An intact homeobox domain is required for complete nuclear localization of human Nanog.

Nanog is a homeobox-containing transcriptional factor required for maintaining the pluripotent state of stem cells. We investigated the nuclear localization signal (NLS) motif required for human Nanog (hNanog) nuclear import. Mutation analysis revealed that a mutant containing only the homeodomain (HD) was exclusively localized to the nucleus, while other mutants containing either the N- or C-terminal region (NR or CR) had impaired nuclear localization. In addition, NR and CR were exclusively localized to the nucleus when they were fused to the HD, indicating that complete nuclear localization is only driven by functional NLS motif(s) within the HD. Furthermore, partial loss of HD led to the incomplete localization of hNanog, suggesting that the intact HD is required for hNanog nuclear import. A series of deletion and site-directed mutagenesis within the HD revealed that two basic NLS motifs are located at the N-terminus and C-terminus of the HD and that both motifs are required for complete hNanog nuclear localization.

Amino Acid Sequence↗

PubMed1996

Preparation of plasmid DNA in transfection complexes for fluorescence and electron spectroscopic imaging.

The aim of this project was to develop procedures necessary to study mechanisms of receptor mediated gene transfer by means of integrated microscopy. Plasmid DNA was incorporated into a transfection complex consisting of poly(L)lysine and transferrin to which the nuclear localization signal was conjugated. This complex was presented to cultured glioma cells. Preparation of the transfected DNA for imaging was pursued by two methods. In the first method tetramethylrhodamine, nanogold, and ferritin were linked through streptavidin to the biotinylated plasmid DNA. Trafficking of the fluorescent derivatives was studied in living cells with fluorescence microscopy. Then, selected cells were rapidly cryo-immobilized. Ultra-structural distribution of the transfected DNA was imaged with energy filtering transmission electron microscopy. In the second method, the unmodified transfected DNA was detected in cryo-immobilized cells by in situ polymerase chain reaction and in situ hybridization. For laser scanning fluorescence microscopy probes were labeled with tetramethylrhodamine. For ultrastructural analysis by electron spectroscopic imaging, probes containing incorporated digoxigenin were labeled with anti-digoxigenin boronated antibodies. Based upon the developed procedures, it has been demonstrated that the presence of the nuclear localization signal in the transfection complex resulted in rapid nuclear import of the transfected DNA.

Cryopreservation↗

PubMed1994

Nuclear accumulation of interferon gamma.

Examination of the interferon gamma (IFN-gamma) amino acid sequence revealed two conserved basic amino acid clusters similar to the prototype nuclear localization signal. We followed the fate of cell surface receptor-bound IFN-gamma in murine leukemia L1210 cells. A time- and temperature-dependent accumulation of murine IFN-gamma in the cell nucleus could be demonstrated by autoradiography and indirect immunofluorescence after the rapid isolation of nuclei. Human IFN-gamma was also internalized and translocated to the nucleus of murine L1210 cells transfected with and expressing the human IFN-gamma receptor, but it appeared to be retained by the nucleus only transiently. IFN-gamma molecules chemically crosslinked to their cell surface receptor remain capable of being translocated to the nucleus even as part of a receptor-ligand complex. Thus, the bipartite nuclear localization signal sequence appears to be functional and suggests that nuclear targeting could participate in IFN-gamma signal transduction.

Animals↗

PubMed1997

Cloning and molecular characterization of an Arabidopsis thaliana RING zinc finger gene expressed preferentially during seed development.

The RING (Really Interesting New Gene) finger is a zinc-binding domain that is found in proteins from a variety of species. This paper reports the cloning and characterization of, as yet, only the second RING finger protein gene from plants, A-RZE, in Arabidopsis thaliana. In addition to the RING-finger motif, A-RZF also contains a putative nuclear localization signal. A-RZF is encoded by a single copy gene with an intron of 595 bp interrupting the 5' leader sequence and the coding region. Northern blot analysis indicated that A-RZF is expressed preferentially during seed development. The RING-finger motif, putative nuclear localization signal, and unique expression pattern, predict an important role during seed development for A-RZF.

Amino Acid Sequence↗

PubMed2002

Characterization of functional regions for nuclear localization of NPAT.

NPAT plays a role in S phase entry as a substrate of cyclin E-CDK2 and activation of histone gene transcription. Although analysis of its sequence indicates that NPAT contains typical nuclear localization signals (NLS) comprising segments of positively charged amino acids, there are currently no experimental data to show that these predictive NLS are functional. To investigate whether these sequences are effective for nuclear transport of NPAT, an NPAT-green fluorescent protein fusion (NP-GFP) was constructed. After transfection of the fusion gene containing the full coding region of NPAT into cultured cells, the NP-GFP product was found exclusively in the nucleus. As expected, some deletion mutants that retained the basic amino acid clusters at the carboxyl terminus also localize the fusion protein in the nucleus. However, other fusions that lacked one of the three basic amino acid-clusters were distributed throughout the nucleus and cytoplasm. Therefore all three clusters of basic residues are necessary for localization of NPAT to the nucleus. However, another sequence outside the carboxyl terminal region functions similarly to NLS. Construction of GFP fusions with a series of truncated forms of NPAT indicated that a short peptide sequence consisting of mainly hydrophobic amino acids near the central domain of NPAT also contributes to localizing the protein in the nucleus.

Active Transport, Cell Nucleus↗

PubMed2001

Nucleo-cytoplasmic trafficking of metal-regulatory transcription factor 1 is regulated by diverse stress signals.

The metal-regulatory transcription factor 1 (MTF-1) is a key regulator of heavy metal-induced transcription of metallothionein I and II and other genes in mammals and other metazoans. Transcriptional activation of genes by MTF-1 is mediated through binding to metal-responsive elements of consensus TGCRCNC in the target gene promoters. In an attempt to further clarify the mechanisms by which certain external signals activate MTF-1 and in turn modulate gene transcription, we show here that human MTF-1 has a dual nuclear and cytoplasmic localization in response to diverse stress stimuli. MTF-1 contains a consensus nuclear localization signal located just N-terminal to the first zinc finger that contributes to but is not essential for nuclear import. MTF-1 also harbors a leucine-rich, nuclear export signal. Under resting conditions, the nuclear export signal is required for cytoplasmic localization of MTF-1 as indicated by mutational analysis and transfer to the heterologous green fluorescent protein. Export from the nucleus was inhibited by leptomycin B, suggesting the involvement of the nuclear export protein CRM1. Our results further show that in addition to the heavy metals zinc and cadmium, heat shock, hydrogen peroxide, low extracellular pH (pH 6.0), inhibition of protein synthesis by cycloheximide, and serum induce nuclear accumulation of MTF-1. However, heavy metals alone (and not the other stress conditions) induce a significant transcriptional response via metal-responsive element promoter sequences, implying that nuclear import of MTF-1 is necessary but not sufficient for transcriptional activation. Possible roles for nuclear import under non-metal stress conditions are discussed.

Cadmium↗

PubMed2000

The transport mechanism of metallothionein is different from that of classical NLS-bearing protein.

A nuclear localization signal (NLS) has been detected in several nuclear proteins. Classical NLS-mediated nuclear pore targeting is performed by using the cytosolic factors, importin alpha and importin beta, whereas nuclear translocation requires the small GTPase, Ran. In the present study, we demonstrated that nuclear localization of metallothionein (MT) differs from that of classical NLS-mediated substrates. In digitonin-permeabilized BALB/c3T3 cells, biotinylated MT was localized in the nucleus in the presence of ATP and erythrocyte cytosol in the same manner as for SV40 large T NLS-conjugated allophycocyanin (APC-NLS). Under ATP-free conditions, nuclear rim-binding was observed in both transport substrates. Rim-binding of labeled MT was competitively inhibited by the addition of an excess amount of unlabeled MT. Different elution profiles were observed for the localization-promoting activities of MT in the cytosol compared to those of APC-NLS. Furthermore, nuclear localization of MT was determined to be a wheat germ agglutinin-insensitive, GTPgammaS-sensitive, and anti-Ran antibody-sensitive process. Green fluorescent protein-metallothionein (GFP-MT) fusion protein was also localized in the nucleus in the stable transformant of CHL-IU cells. These results strongly suggest that the targeting by MT of the nuclear pore is mediated by cytosolic factor(s) other than importins and that MT requires Ran for its nuclear localization.

3T3 Cells↗

PubMed1992

Nuclear and nucleolar targeting signals of Semliki Forest virus nonstructural protein nsP2.

Semliki Forest virus nonstructural protein nsP2, when expressed in the absence of other viral proteins, is transported into the nucleus, with a specific enrichment in nucleoli. This implies that information for its nuclear targeting must be in nsP2 itself. To define the nuclear and nucleolar targeting signals of nsP2, a series of in-frame deletions were made in its coding sequence. We have identified one amino-terminal (residues 25-110) and another carboxy-terminal (residues 634-661) deletion, both of which rendered nsP2 cytoplasmic. The carboxy-terminal region had a pentapeptide sequence P 648R RRV, which resembles some of the known nuclear localization signals. When the three arginines were substituted with aspartic acids, the mutant nsP2 was localized in the cytoplasm. Especially arginines 648-649 were shown to be critical. The carboxy-terminal 232 amino acid residues of nsP2 were able to translocate beta-galactosidase to the nucleus as a fusion protein, whereas the amino-terminal 110 residues failed to do so. Studies with different beta-galactosidase-nsP2 fusions showed that the pentapeptide is necessary for nuclear transport but that its activity is strongly affected by the context. The deletion analysis indicated also that the nuclear localization signal was not sufficient for nucleolar targeting of nsP2. The nucleolar targeting sequence of nsP2 was tentatively mapped between residues 470 and 539, and at least residues 470-489 are an essential part of it.

Animals↗

PubMed1988

Two nuclear location signals in the influenza virus NS1 nonstructural protein.

The NS1 protein of influenza A virus has been shown to enter and accumulate in the nuclei of virus-infected cells independently of any other influenza viral protein. Therefore, the NS1 protein contains within its polypeptide sequence the information that codes for its nuclear localization. To define the nuclear signal of the NS1 protein, a series of recombinant simian virus 40 vectors that express deletion mutants or fusion proteins was constructed. Analysis of the proteins expressed resulted in identification of two regions of the NS1 protein which affect its cellular location. Nuclear localization signal 1 (NLS1) contains the stretch of basic amino acids Asp-Arg-Leu-Arg-Arg (codons 34 to 38). This sequence is conserved in all NS1 proteins of influenza A viruses, as well as in that of influenza B viruses. NLS2 is defined within the region between amino acids 203 and 237. This domain is present in the NS1 proteins of most influenza A virus strains. NLS1 and NLS2 contain basic amino acids and are similar to previously defined nuclear signal sequences of other proteins.

Amino Acid Sequence↗