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Results for “Nuclear Export Signals”

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PubMed2006

Apoptin nucleocytoplasmic shuttling is required for cell type-specific localization, apoptosis, and recruitment of the anaphase-promoting complex/cyclosome to PML bodies.

The chicken anemia virus protein Apoptin selectively induces apoptosis in transformed cells while leaving normal cells intact. This selectivity is thought to be largely due to cell type-specific localization: Apoptin is cytoplasmic in primary cells and nuclear in transformed cells. The basis of Apoptin cell type-specific localization and activity remains to be determined. Here we show that Apoptin is a nucleocytoplasmic shuttling protein whose localization is mediated by an N-terminal nuclear export signal (NES) and a C-terminal nuclear localization signal (NLS). Both signals are required for cell type-specific localization, since Apoptin fragments containing either the NES or the NLS fail to differentially localize in transformed and primary cells. Significantly, cell type-specific localization can be conferred in trans by coexpression of the two separate fragments, which interact through an Apoptin multimerization domain. We have previously shown that Apoptin interacts with the APC1 subunit of the anaphase-promoting complex/cyclosome (APC/C), resulting in G(2)/M cell cycle arrest and apoptosis in transformed cells. We found that the nucleocytoplasmic shuttling activity is critical for efficient APC1 association and induction of apoptosis in transformed cells. Interestingly, both Apoptin multimerization and APC1 interaction are mediated by domains that overlap with the NES and NLS sequences, respectively. Apoptin expression in transformed cells induces the formation of PML nuclear bodies and recruits APC/C to these subnuclear structures. Our results reveal a mechanism for the selective killing of transformed cells by Apoptin.

Active Transport, Cell Nucleus↗

PubMed2000

Characterization of the interaction between the interferon-induced protein P56 and the Int6 protein encoded by a locus of insertion of the mouse mammary tumor virus.

For determining cellular functions of the interferon-inducible human cytoplasmic protein P56, we undertook a Saccharomyces cerevisiae two-hybrid screen that identified Int6 as a P56-interacting protein. That the interaction also occurs in human cells was confirmed by coimmunoprecipitation and the observed cytoplasmic displacement of nuclear Int6 upon coexpression of P56. Because Int6 has been claimed to be both a cytoplasmic and a nuclear protein, we investigated the structural basis of this discrepancy. By mutational analyses, we showed that the Int6 protein contains a bipartite nuclear localization signal and a nuclear export signal at the far end of the amino terminus. The 20 amino-terminal residues of Int6, when they were attached to a different nuclear protein, were sufficient to translocate that protein to the cytoplasm. Within this region, replacement of any of the three leucine residues with alanine destroyed the function of the export signal. The specific domain of P56 that is required for its interaction with Int6 was mapped using the yeast two-hybrid assay and a mammalian coimmunoprecipitation assay. Both assays demonstrated that the C-terminal region of P56 containing three specific tetratricopeptide motifs is required for this interaction. In contrast, removal of an internal domain of P56 enhanced the interaction, as quantified by the two-hybrid assay.

Adaptor Proteins, Signal Transducing↗

PubMed2006

p204 is required for the differentiation of P19 murine embryonal carcinoma cells to beating cardiac myocytes: its expression is activated by the cardiac Gata4, Nkx2.5, and Tbx5 proteins.

Among 10 adult mouse tissues tested, the p204 protein levels were highest in heart and skeletal muscle. We described previously that the MyoD-inducible p204 protein is required for the differentiation of cultured murine C2C12 skeletal muscle myoblasts to myotubes. Here we report that p204 was also required for the differentiation of cultured P19 murine embryonal carcinoma stem cells to beating cardiac myocytes. As shown by others, this process can be triggered by dimethyl sulfoxide (DMSO). We established that DMSO induced the formation of 204RNA and p204. Ectopic p204 could partially substitute for DMSO in inducing differentiation, whereas ectopic 204 antisense RNA inhibited the differentiation. Experiments with reporter constructs, including regulatory regions from the Ifi204 gene (encoding p204) in P19 cells and in cultured newborn rat cardiac myocytes, as well as chromatin coimmunoprecipitations with transcription factors, revealed that p204 expression was synergistically transactivated by the cardiac Gata4, Nkx2.5, and Tbx5 transcription factors. Furthermore, ectopic p204 triggered the expression of Gata4 and Nkx2.5 in P19 cells. p204 contains a nuclear export signal and was partially translocated to the cytoplasm during the differentiation. p204 from which the nuclear export signal was deleted was not translocated, and it did not induce differentiation. The various mechanisms by which p204 promoted the differentiation are reported in the accompanying article (Ding, B., Liu, C., Huang, Y., Yu, J., Kong, W., and Lengyel, P. (2006) J. Biol. Chem. 281, 14893-14906).

Amino Acid Sequence↗

PubMed2001

The balance of nuclear import and export determines the intracellular distribution and function of tomato heat stress transcription factor HsfA2.

Tomato heat stress transcription factor HsfA2 is a shuttling protein with dominant cytoplasmic localization as a result of a nuclear import combined with an efficient export. Besides the nuclear localization signal (NLS) adjacent to the oligomerization domain, a C-terminal leucine-rich motif functions as a nuclear export signal (NES). Mutant forms of HsfA2 with a defective or an absent NES are nuclear proteins. The same is true for the wild-type HsfA2 if coexpressed with HsfA1 or in the presence of export inhibitor leptomycin B (LMB). Fusion of the NES domain of HsfA2 to HsfB1, which is a nuclear protein, caused export of the HsfB1-A2NES hybrid protein, and this effect was reversed by the addition of LMB. Due to the lack of background problems, Chinese hamster ovary (CHO) cells represent an excellent system for expression and functional analysis of tomato Hsfs. The results faithfully reflect the situation found in plant cells (tobacco protoplasts). The intriguing role of NLS and NES accessibility for the intracellular distribution of HsfA2 is underlined by the results of heat stress treatments of CHO cells (41 degrees C). Despite the fact that nuclear import and export are not markedly affected, HsfA2 remains completely cytoplasmic at 41 degrees C even in the presence of LMB. The temperature-dependent conformational transition of HsfA2 with shielding of the NLS evidently needs intramolecular interaction between the internal HR-A/B and the C-terminal HR-C regions. It is not observed with the HR oligomerization domain (HR-A/B region) deletion form of HsfA2 or in HsfA2-HsfA1 hetero-oligomers.

Animals↗

PubMed1999

Export of galectin-3 from nuclei of digitonin-permeabilized mouse 3T3 fibroblasts.

Galectin-3 is a galactose-/lactose-binding protein (M(r) approximately 30,000), identified as a required factor in the splicing of pre-mRNA. Immunofluorescence staining revealed that galectin-3 distributes differentially between the nucleus and the cytoplasm, depending on the proliferative state of the cells under analysis. Using digitonin-permeabilized mouse 3T3 fibroblasts, we provide evidence that galectin-3 is rapidly and selectively exported from the nucleus. Although both phosphorylated and nonphosphorylated isoforms of galectin-3 are found in the nuclear fraction, only phosphorylated galectin-3 is identified in the exported fraction, implying that phosphorylation is important for the nuclear export of the protein. The rate of galectin-3 export is temperature dependent and is decreased by the addition of wheat germ agglutinin. More strikingly, galectin-3 export can be inhibited by the addition of leptomycin B, a drug that disrupts the interaction between the leucine-rich nuclear export signal and its receptor, CRM1 (chromosome maintenance region 1). Indeed, a putative leucine-rich nuclear export signal can be found in residues 241-249 of the murine galectin-3 sequence. Finally, gel filtration of the exported material showed that galectin-3 can be found in at least two high molecular weight complexes (approximately 650 and approximately 60 kDa), both of which can be disrupted by lactose.

3T3 Cells↗

PubMed2006

AKT can be activated in the nucleus.

To investigate issues about AKT/PKB nuclear localization in cells, we examined endogenous or transiently transfected AKT localization in cancer cell lines by immunofluorescence. We found that AKT can be detected in both the nucleus and cytoplasm of HEK 293, HeLa and MCF7E cells. It was found that an active process mediates AKT nuclear translocation as shown by fusing AKT with GFP3 protein. The cellular distribution pattern of serial deletion mutants from GFP3-HA-AKT revealed that more than one segment of AKT is required for AKT nuclear translocation, while the individual segment does not have any apparent nuclear transport activity. These results implied that the signal mediating AKT nuclear translocation is conformation dependent, or more likely, is dependent upon association with other proteins. It was also found that AKT does not contain any apparent nuclear export signal. Furthermore, we found that nuclear AKT was activated in MCF7E cells upon stimulation. The possibility that nuclear activated AKT was translocated from the cytoplasm was excluded through the generation of a chimeric AKT protein, in which a strong nuclear localization signal was fused to the C-terminal of AKT.

Active Transport, Cell Nucleus↗

PubMed2005

The carboxyl-terminal segment of the adaptor protein ALX directs its nuclear export during T cell activation.

The adaptor protein ALX acts downstream of CD28 to regulate the interleukin-2 (IL-2) promoter during T cell activation. Whereas ALX is predominantly localized to the cytoplasm, ALX partially resides in the nucleus, and the nuclear pool is rapidly depleted in response to T cell receptor (TCR)/CD28 signaling. Here it is shown that this depletion occurs via nuclear export of ALX, which depends on a leucine-rich nuclear export signal (NES) in its carboxyl segment and on the CRM-1 transport protein. Nuclear import of ALX also depends on its carboxyl-terminal segment. Blocking nuclear export of ALX, either pharmacologically, by leptomycin B, or by site-directed mutation of the ALX NES, impairs CD28-mediated phosphorylation of ALX. Additionally, upon overexpression, the ALX NES mutant was found to be impaired in inhibiting TCR/CD28-induced transcriptional up-regulation of the RE/AP composite element from the IL-2 promoter, whereas a truncated form of ALX that is a potent inhibitor of RE/AP activation was found to reside entirely in the cytoplasm. Together, these results show that ALX exerts its effect on IL-2 up-regulation in the cytoplasm and suggest an intricate relationship between the nuclear localization/export, phosphorylation, and activity of ALX in response to TCR and CD28 signaling.

Active Transport, Cell Nucleus↗

PubMed1999

Nuclear import and export: transport factors, mechanisms and regulation.

Molecules enter and exit the nucleus of eukaryotic cells through aqueous channels formed in the nuclear envelope by nuclear pore complexes (NPC). Proteins entering or leaving the nucleus use nuclear localization signals (NLSs), or nuclear export signals (NESs), respectively. Different types of NLSs and NESs are specifically recognized directly, or indirectly via adapters, by transport receptors. In recent years, many transport receptors, adapters, and the specific cargoes they carry into or out of the nucleus have been identified, revealing an increasing level of complexity. All the transport receptors identified are members of the same family and have in common the ability to shuttle between the nucleus and cytoplasm, and to interact with RanGTP and with nucleoporins at the NPC. The GTPase Ran regulates the interaction between receptors and cargoes, or adapters, and is crucial in providing directionality to nuclear import and export. One of the challenges for the future will be establishing the mechanisms of translocation through the NPC of receptors together with their cargoes. Nuclear import and export of many cargoes is regulated. The molecular mechanisms of regulation of nucleocytoplasmic transport during cell growth, development, viral infections, and different diseases constitute important areas of investigation.

Biological Transport↗

PubMed1997

Multiple protein domains determine the cell type-specific nuclear distribution of the catalytic subunit required for apolipoprotein B mRNA editing.

Apolipoprotein B (apoB) mRNA editing catalyzed by apoB mRNA editing catalytic subunit 1 (APOBEC-1) has been proposed to be a nuclear process. To test this hypothesis, the subcellular distribution of hemagglutinin- (HA) tagged APOBEC-1 expressed in transiently transfected hepatoma cells was determined by indirect immunofluorescence microscopy. HA-APOBEC-1 was detected in both the nucleus and cytoplasm of rat and human hepatoma cells. Mutagenesis of APOBEC-1 demonstrated that the N-terminal 56 amino acids (1-56) were necessary for the nuclear distribution of APOBEC-1, but this region did not contain a functional nuclear localization signal (NLS). However, we identified a 24-amino acid domain in the C terminus of APOBEC-1 with characteristics of a cytoplasmic retention signal (CRS) or a nuclear export signal (NES). These data suggest, therefore, that the nuclear import of APOBEC-1 may not be mediated by a positive NLS; rather, it may be achieved by overcoming the effect of a CRS/NES. We also demonstrated that the nuclear distribution of APOBEC-1 occurred only in cell lines that were capable of editing apoB RNA. We propose that the cellular distribution of APOBEC-1 is determined by multiple domains within this protein, and a nuclear localization of the enzyme may be regulated by cell type-specific factors that render these cells uniquely editing competent.

APOBEC-1 Deaminase↗

PubMed2003

A docking site determining specificity of Pbs2 MAPKK for Ssk2/Ssk22 MAPKKKs in the yeast HOG pathway.

Mitogen-activated protein kinase (MAPK) cascades are conserved signaling modules composed of three sequentially activated kinases (MAPKKK, MAPKK and MAPK). Because individual cells contain multiple MAPK cascades, mechanisms are required to ensure the fidelity of signal transmission. In yeast, external high osmolarity activates the HOG (high osmolarity glycerol) MAPK pathway, which consists of two upstream branches (SHO1 and SLN1) and common downstream elements including the Pbs2 MAPKK and the Hog1 MAPK. The Ssk2/Ssk22 MAPKKKs in the SLN1 branch, when activated, exclusively phosphorylate the Pbs2 MAPKK. We found that this was due to an Ssk2/Ssk22-specific docking site in the Pbs2 N-terminal region. The Pbs2 docking site constitutively bound the Ssk2/Ssk22 kinase domain. Docking site mutations drastically reduced the Pbs2-Ssk2/Ssk22 interaction and hampered Hog1 activation by the SLN1 branch. Fusion of the Pbs2 docking site to a different MAPKK, Ste7, allowed phosphorylation of Ste7 by Ssk2/Ssk22. Thus, the docking site contributes to both the efficiency and specificity of signaling. During these analyses, we also found a nuclear export signal and a possible nuclear localization signal in Pbs2.

Amino Acid Sequence↗

PubMed2001

Regulation of subcellular localization of the aryl hydrocarbon receptor (AhR).

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity of dioxin and other xenobiotics. In the absence of exogenous ligand, AhR is cytosolic. We investigated how AhR is retained in the cytosol and how dioxin induces AhR to move to the nucleus. Disruption of nuclear export of AhR by the nuclear export inhibitor leptomycin B (LMB) or by mutation of the AhR nuclear export signal resulted in nuclear accumulation of AhR in the absence of exogenous ligand. Mutation of the AhR nuclear localization signal resulted in defects in nuclear import of AhR in both the presence and the absence of exogenous ligand. Dioxin treatment caused a more rapid accumulation of AhR in the nucleus than LMB treatment. In the presence of both dioxin and LMB, nuclear accumulation of AhR was more rapid than in the presence of dioxin alone. Our results show that AhR shuttles between the nucleus and the cytosol in the absence of exogenous ligand. Binding of ligand induces an increase in the rate of nuclear import of AhR but does not eliminate nuclear export of AhR.

Active Transport, Cell Nucleus↗

PubMed1994

Nuclear export of signal recognition particle RNA is a facilitated process that involves the Alu sequence domain.

The signal recognition particle is a cytoplasmic RNA-protein complex that mediates translocation of secretory polypeptides into the endoplasmic reticulum. We have used a Xenopus oocyte microinjection assay to determine how signal recognition particle (SRP) RNA is exported from the nucleus. Following nuclear injection, SRP RNA accumulated in the cytoplasm while cytoplasmically injected SRP RNA did not enter the nucleus. Cytoplasmic accumulation of SRP RNA was an apparently facilitated process dependent on limiting trans-acting factors, since nuclear export exhibited saturation kinetics and was completely blocked either at low temperature or by wheat germ agglutinin, a known inhibitor of nuclear pore-mediated transport. At least one target for trans-acting factors that promote nuclear export of SRP RNA appears to be the Alu element of the molecule, since a transcript consisting of only the Alu sequence was exported from the nucleus in a temperature-dependent manner and the Alu transcript competed in the nucleus for transport with intact SRP RNA. Although the identities of trans-acting factors responsible for SRP RNA transport are at present unknown, we suggest that proteins contained within the cytoplasmic form of SRP are candidates. Consistent with this idea were the effects of a mutation in SRP RNA that prevented binding of two known SRP proteins to the Alu sequence.

Animals↗

PubMed1999

Direct observation of nucleocytoplasmic transport by microinjection of GFP-tagged proteins in living cells.

We established a straightforward experimental system to investigate directly the requirements for nucleocytoplasmic transport in live cells. For this purpose, substrates were created containing nuclear localization signals (NLS) or nuclear export signals (NES) linked to a chimeric protein composed of the glutathione S-transferase (GST) fused to the green fluorescent protein (GFP). The combination of GST/GFP-tagging allowed us to control protein expression in bacteria and to monitor protein purification during chromatography. Following microinjection into somatic cells, nuclear export/import of the highly fluorescent substrates could be observed directly by fluorescence microscopy. This system sets the stage to quantitate, in real time, the kinetics of nuclear import/export in living cells and to evaluate qualitative differences in various NLS/NES signals and pathways.

Animals↗

PubMed2006

Gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25) is a transport protein involved in gene-specific mRNA export and protein translation during spermatogenesis.

Gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25), a member of the DEAD-box protein family, is essential for completion of spermatogenesis. GRTH is present in the cytoplasm and nucleus of meiotic spermatocytes and round spermatids and functions as a component of mRNP particles, implicating its post-transcriptional regulatory roles in germ cells. In this study, GRTH antibodies specific to N- or C-terminal sequences showed differential subcellular expression of GRTH 56- and 61-kDa species in nucleus and cytoplasm, respectively, of rodent testis and transfected COS1 cells. The 56-kDa nuclear species interacted with CRM1 and participated in mRNA transport. The phosphorylated cytoplasmic 61-kDa species was associated with polyribosomes. Confocal studies on COS-1 cells showed that GRTH-GFP was retained in the nucleus by treatment with a RNA polymerase inhibitor or the nuclear protein export inhibitor. This indicated that GRTH is a shuttling protein associated with RNA export. The N-terminal leucine-rich region (61-74 amino acids) was identified as the nuclear export signal that participated in CRM1-dependent nuclear export pathway. Deletion analysis identified a 14-amino acid GRTH sequence (100-114 amino acids) as a nuclear localization signal. GRTH selectively regulated the translation of specific genes including histone 4 and HMG2 in germ cells. In addition, GRTH participated in the nuclear export of RNA messages (PGK2, tACE, and TP2) in a gene-specific manner. These studies strongly indicate that the mammalian GRTH/Ddx25 gene is a multifunctional RNA helicase that is an essential regulator of sperm maturation.

Animals↗

PubMed2004

STAT2 nuclear trafficking.

STAT2 is a transcription factor critical to the signal transduction pathway of type I interferons (e.g. IFNalpha). STAT2 resides primarily in the cytoplasm and is tyrosine-phosphorylated after IFNalpha binds to cell surface receptors. In response to tyrosine phosphorylation STAT2 rapidly localizes to the nucleus and acquires the ability to bind specific DNA targets in association with two other proteins, STAT1 and IFN regulatory factor-9 (IRF-9). To elucidate the mechanisms that regulate cellular localization of STAT2, we investigated STAT2 nuclear trafficking both prior to tyrosine phosphorylation and after phosphorylation. Prior to phosphorylation, STAT2 is primarily resident in the cytoplasm, however, we found that it dynamically shuttles between nuclear and cytoplasmic compartments. The nuclear translocation of latent unphosphorylated STAT2 was found to be dependent on its constitutive association with IRF-9, and the export of STAT2 from the nucleus was contingent upon the function of an intrinsic nuclear export signal within the carboxyl terminus of STAT2. STAT2 export could be inhibited with leptomycin B, indicating a nuclear export signal within STAT2 is recognized by the CRM1 exportin carrier. In contrast, following tyrosine phosphorylation, STAT2 dimerizes with phosphorylated STAT1 and accumulates in the nucleus. In the absence of STAT1, STAT2 does not accumulate in the nucleus. In addition, subsequent to nuclear import of phosphorylated STAT2, it redistributes to the cytoplasm within an hour coordinate with its dephosphorylation in the nucleus. The regulation of STAT2 nuclear trafficking is distinct from the previously characterized STAT1 factor.

Cell Line, Tumor↗

PubMed2006

Inhibition of nuclear import of calcineurin prevents myocardial hypertrophy.

The time that transcription factors remain nuclear is a major determinant for transcriptional activity. It has recently been demonstrated that the phosphatase calcineurin is translocated to the nucleus with the transcription factor nuclear factor of activated T cells (NF-AT). This study identifies a nuclear localization sequence (NLS) and a nuclear export signal (NES) in the sequence of calcineurin. Furthermore we identified the nuclear cargo protein importinbeta(1) to be responsible for nuclear translocation of calcineurin. Inhibition of the calcineurin/importin interaction by a competitive peptide (KQECKIKYSERV), which mimicked the calcineurin NLS, prevented nuclear entry of calcineurin. A noninhibitory control peptide did not interfere with the calcineurin/importin binding. Using this approach, we were able to prevent the development of myocardial hypertrophy. In angiotensin II-stimulated cardiomyocytes, [(3)H]-leucine incorporation (159%+/-9 versus 111%+/-11; P<0.01) and cell size were suppressed significantly by the NLS peptide compared with a control peptide. The NLS peptide inhibited calcineurin/NF-AT transcriptional activity (227%+/-11 versus 133%+/-8; P<0.01), whereas calcineurin phosphatase activity was unaffected (298%+/-9 versus 270%+/-11; P=NS). We conclude that calcineurin is not only capable of dephosphorylating NF-AT, thus enabling its nuclear import, but the presence of calcineurin in the nucleus is also important for full NF-AT transcriptional activity.

Active Transport, Cell Nucleus↗

PubMed2004

hnRNP L enhances sensitivity of the cells to KW-2189.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are involved in several RNA-related biological processes. We demonstrated hnRNP L as a candidate protein of DARP (duocarmycin-DNA adduct recognizing protein) by gel shift assay and amino acid sequencing. Stable transfectants of hnRNP L showed high sensitivity of the cells to the growth inhibitory effect of KW-2189, a duocarmycin derivative in vitro. Immunostaining of hnRNP L demonstrated differential intracellular localization of hnRNP L among human lung cancer cell lines. A transfection study using a series of deletion mutants of hnRNP L fused to indicated that the N-terminal portions of RRM(RNA recognition motif)1, RRM3 and RRM2 are involved in localization of hnRNP L. We identified sequences in these portions that have high homology with the sequences of known NLS (nuclear localization signal) and NES (nuclear export signal). hnRNP L is a factor that determines the sensitivities of cancer cells to the minor groove binder, and overexpression and differential intracellular localization of hnRNP L are involved in its function in lung cancer.

Amino Acid Sequence↗

PubMed2006

EcR and Usp, components of the ecdysteroid nuclear receptor complex, exhibit differential distribution of molecular determinants directing subcellular trafficking.

Ecdysteroids coordinate development, reproduction and other essential biological processes in insects and other arthropods through the receptor which is a heterodimer of two members of the nuclear receptors superfamily, the ecdysteroid receptor (EcR) and the Ultraspiracle (Usp). Although the transcriptionally active EcR/Usp heterocomplex is believed to be the only functional form of the receptor, there are data indicating that EcR may be involved in the mediation of the non-genomic effects outside of the nucleus. Since the nucleocytoplasmic shuttling could be a key element determining participation of the single nuclear receptor molecule both in the genomic and non-genomic functions we have analyzed nuclear import and export properties of the EcR and Usp from Drosophila melanogaster. We show for the first time that both receptors exhibit differential distribution of the nuclear localization and nuclear export signals (NLSs and NESs). In particular, the Usp which exhibits exclusively nuclear localization in all cell types analyzed, contains apparently only NLS activity within the DNA-binding domain. In contrast, the three known EcR isoforms (A, B1 and B2) are mosaics of elements which can potentially mediate their nucleocytoplasmic shuttling. We have found two active NESs in ligand binding domain and NLS activity within the DNA-binding domain of all isoforms. Simultaneously we demonstrate that B1 and A isoforms possess an additional NLS activity localized in AB regions. We speculate that this characteristic, along with the previously reported structural pliability of the EcR molecule, allows the single receptor to evoke many different genomic as well as non-genomic ecdysteroid-dependent responses.

Active Transport, Cell Nucleus↗