The Experts below are selected from a list of 7035 Experts worldwide ranked by ideXlab platform
Thomas Stamminger - One of the best experts on this subject based on the ideXlab platform.
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a novel transferable Nuclear Export Signal mediates crm1 independent nucleocytoplasmic shuttling of the human cytomegalovirus transactivator protein pul69
The EMBO Journal, 2001Co-Authors: Peter Lischka, Olaf Rosorius, Erik Trommer, Thomas StammingerAbstract:The best studied Nuclear Export processes are mediated by classical leucine-rich Nuclear Export Signals that specify recognition by the CRM1 Export receptor. However, details concerning alternative Nuclear Export Signals and pathways are beginning to emerge. Within the family of Herpesviridae, a set of homologous regulatory proteins that are exemplified by the ICP27 of herpes simplex virus were described recently as nucleocytoplasmic shuttling proteins. Here we report that pUL69 of the β-herpesvirus human cytomegalovirus is a Nuclear protein that is able to shuttle between the nucleus and the cytoplasm independently of virus-encoded cofactors. In contrast to proteins containing a leucine-rich Export Signal, the shuttling activity of pUL69 was not affected by leptomycin B, indicating that pUL69 trafficking is not mediated by the Export receptor CRM1. Importantly, we identified and characterized a novel type of transferable, leptomycin B-insensitive Export Signal that is distinct from other Export Signals described previously and is required for pUL69-mediated activation of gene expression. These data suggest that pUL69 is Exported via a novel Nuclear Export pathway, based on a so far unique Nuclear Export Signal of 28 amino acids.
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A novel transferable Nuclear Export Signal mediates CRM1‐independent nucleocytoplasmic shuttling of the human cytomegalovirus transactivator protein pUL69
The EMBO journal, 2001Co-Authors: Peter Lischka, Olaf Rosorius, Erik Trommer, Thomas StammingerAbstract:The best studied Nuclear Export processes are mediated by classical leucine-rich Nuclear Export Signals that specify recognition by the CRM1 Export receptor. However, details concerning alternative Nuclear Export Signals and pathways are beginning to emerge. Within the family of Herpesviridae, a set of homologous regulatory proteins that are exemplified by the ICP27 of herpes simplex virus were described recently as nucleocytoplasmic shuttling proteins. Here we report that pUL69 of the β-herpesvirus human cytomegalovirus is a Nuclear protein that is able to shuttle between the nucleus and the cytoplasm independently of virus-encoded cofactors. In contrast to proteins containing a leucine-rich Export Signal, the shuttling activity of pUL69 was not affected by leptomycin B, indicating that pUL69 trafficking is not mediated by the Export receptor CRM1. Importantly, we identified and characterized a novel type of transferable, leptomycin B-insensitive Export Signal that is distinct from other Export Signals described previously and is required for pUL69-mediated activation of gene expression. These data suggest that pUL69 is Exported via a novel Nuclear Export pathway, based on a so far unique Nuclear Export Signal of 28 amino acids.
Katherine L B Borden - One of the best experts on this subject based on the ideXlab platform.
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a tfeb Nuclear Export Signal integrates amino acid supply and glucose availability
Nature Communications, 2018Co-Authors: Linxin Li, Hans Friedrichsen, Kao Chin Ngeow, Georgina Berridge, Laurent Volpon, Roman Fischer, Sarah Picaud, Sarah Andrews, Katherine L B BordenAbstract:How cells coordinate the response to fluctuating carbon and nitrogen availability required to maintain effective homeostasis is a key issue. Amino acid limitation that inactivates mTORC1 promotes de-phosphorylation and Nuclear translocation of Transcription Factor EB (TFEB), a key transcriptional regulator of lysosome biogenesis and autophagy that is deregulated in cancer and neurodegeneration. Beyond its cytoplasmic sequestration, how TFEB phosphorylation regulates its Nuclear-cytoplasmic shuttling, and whether TFEB can coordinate amino acid supply with glucose availability is poorly understood. Here we show that TFEB phosphorylation on S142 primes for GSK3β phosphorylation on S138, and that phosphorylation of both sites but not either alone activates a previously unrecognized Nuclear Export Signal (NES). Importantly, GSK3β is inactivated by AKT in response to mTORC2 Signaling triggered by glucose limitation. Remarkably therefore, the TFEB NES integrates carbon (glucose) and nitrogen (amino acid) availability by controlling TFEB flux through a Nuclear import-Export cycle. On amino acid deprivation TFEB translocates from the cytoplasm to the nucleus. Here the authors identify a Nuclear Export Signal in TFEB that requires dual phosphorylation at the S142 ERK/mTORC1 and S138 GSK3β sites, and further show glucose limitation drives Nuclear accumulation of TFEB and inhibits GSK3β via an mTORC2-AKT dependent mechanism.
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A TFEB Nuclear Export Signal integrates amino acid supply and glucose availability.
Nature communications, 2018Co-Authors: Hans Friedrichsen, Kao Chin Ngeow, Katherine L B Borden, Georgina Berridge, Laurent Volpon, Roman Fischer, Sarah Picaud, Sarah Andrews, Panagis FilippakopoulosAbstract:How cells coordinate the response to fluctuating carbon and nitrogen availability required to maintain effective homeostasis is a key issue. Amino acid limitation that inactivates mTORC1 promotes de-phosphorylation and Nuclear translocation of Transcription Factor EB (TFEB), a key transcriptional regulator of lysosome biogenesis and autophagy that is deregulated in cancer and neurodegeneration. Beyond its cytoplasmic sequestration, how TFEB phosphorylation regulates its Nuclear-cytoplasmic shuttling, and whether TFEB can coordinate amino acid supply with glucose availability is poorly understood. Here we show that TFEB phosphorylation on S142 primes for GSK3β phosphorylation on S138, and that phosphorylation of both sites but not either alone activates a previously unrecognized Nuclear Export Signal (NES). Importantly, GSK3β is inactivated by AKT in response to mTORC2 Signaling triggered by glucose limitation. Remarkably therefore, the TFEB NES integrates carbon (glucose) and nitrogen (amino acid) availability by controlling TFEB flux through a Nuclear import-Export cycle.
Bryan R. Cullen - One of the best experts on this subject based on the ideXlab platform.
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The Human Tap Nuclear RNA Export Factor Contains a Novel Transportin-dependent Nuclear Localization Signal That Lacks Nuclear Export Signal Function
The Journal of biological chemistry, 1999Co-Authors: Ray Truant, Yibin Kang, Bryan R. CullenAbstract:The human Tap protein mediates the sequence-specific Nuclear Export of RNAs containing the constitutive transport element and is likely also critical for general mRNA Export. Here, we demonstrate that a previously defined arginine-rich Nuclear localization Signal (NLS) present in Tap acts exclusively via the transportin import factor. Previously, transportin has been shown to mediate the Nuclear import of several heterogeneous Nuclear ribonucleoproteins, including heterogeneous Nuclear ribonucleoprotein (hnRNP) A1, by binding to a sequence element termed M9. Although the Tap NLS and the hnRNP A1 M9 element are shown to compete for transportin binding, they show no sequence homology, and the Tap NLS does not conform to the recently defined M9 consensus. The Tap NLS also differs from M9 in that only the latter is able to act as a Nuclear Export Signal. The Tap NLS is therefore the first member of a novel class of transportin-specific NLSs that lack Nuclear Export Signal function.
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AMPHIBIAN TRANSCRIPTION FACTOR IIIA PROTEINS CONTAIN A SEQUENCE ELEMENT FUNCTIONALLY EQUIVALENT TO THE Nuclear Export Signal OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 REV
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Robert A. Fridell, Michael H. Malim, Utz Fischer, Reinhard Lührmann, Barbara E. Meyer, J L Meinkoth, Bryan R. CullenAbstract:The human immunodeficiency virus type 1 (HIV-1) Rev protein is required for Nuclear Export of late HIV-1 mRNAs. This function is dependent on the mutationally defined Rev activation domain, which also forms a potent Nuclear Export Signal. Transcription factor IIIA (TFIIIA) binds to 5S rRNA transcripts and this interaction has been proposed to play a role in the efficient Nuclear Export of 5S rRNA in amphibian oocytes. Here it is reported that amphibian TFIIIA proteins contain a sequence element with homology to the Rev activation domain that effectively substitutes for this domain in inducing the Nuclear Export of late HIV-1 mRNAs. It is further demonstrated that this TFIIIA sequence element functions as a protein Nuclear Export Signal in both human cells and frog oocytes. Thus, this shared protein motif may play an analogous role in mediating the Nuclear Export of both late HIV-1 RNAs and 5S rRNA transcripts.
Georgina Berridge - One of the best experts on this subject based on the ideXlab platform.
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a tfeb Nuclear Export Signal integrates amino acid supply and glucose availability
Nature Communications, 2018Co-Authors: Linxin Li, Hans Friedrichsen, Kao Chin Ngeow, Georgina Berridge, Laurent Volpon, Roman Fischer, Sarah Picaud, Sarah Andrews, Katherine L B BordenAbstract:How cells coordinate the response to fluctuating carbon and nitrogen availability required to maintain effective homeostasis is a key issue. Amino acid limitation that inactivates mTORC1 promotes de-phosphorylation and Nuclear translocation of Transcription Factor EB (TFEB), a key transcriptional regulator of lysosome biogenesis and autophagy that is deregulated in cancer and neurodegeneration. Beyond its cytoplasmic sequestration, how TFEB phosphorylation regulates its Nuclear-cytoplasmic shuttling, and whether TFEB can coordinate amino acid supply with glucose availability is poorly understood. Here we show that TFEB phosphorylation on S142 primes for GSK3β phosphorylation on S138, and that phosphorylation of both sites but not either alone activates a previously unrecognized Nuclear Export Signal (NES). Importantly, GSK3β is inactivated by AKT in response to mTORC2 Signaling triggered by glucose limitation. Remarkably therefore, the TFEB NES integrates carbon (glucose) and nitrogen (amino acid) availability by controlling TFEB flux through a Nuclear import-Export cycle. On amino acid deprivation TFEB translocates from the cytoplasm to the nucleus. Here the authors identify a Nuclear Export Signal in TFEB that requires dual phosphorylation at the S142 ERK/mTORC1 and S138 GSK3β sites, and further show glucose limitation drives Nuclear accumulation of TFEB and inhibits GSK3β via an mTORC2-AKT dependent mechanism.
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A TFEB Nuclear Export Signal integrates amino acid supply and glucose availability.
Nature communications, 2018Co-Authors: Hans Friedrichsen, Kao Chin Ngeow, Katherine L B Borden, Georgina Berridge, Laurent Volpon, Roman Fischer, Sarah Picaud, Sarah Andrews, Panagis FilippakopoulosAbstract:How cells coordinate the response to fluctuating carbon and nitrogen availability required to maintain effective homeostasis is a key issue. Amino acid limitation that inactivates mTORC1 promotes de-phosphorylation and Nuclear translocation of Transcription Factor EB (TFEB), a key transcriptional regulator of lysosome biogenesis and autophagy that is deregulated in cancer and neurodegeneration. Beyond its cytoplasmic sequestration, how TFEB phosphorylation regulates its Nuclear-cytoplasmic shuttling, and whether TFEB can coordinate amino acid supply with glucose availability is poorly understood. Here we show that TFEB phosphorylation on S142 primes for GSK3β phosphorylation on S138, and that phosphorylation of both sites but not either alone activates a previously unrecognized Nuclear Export Signal (NES). Importantly, GSK3β is inactivated by AKT in response to mTORC2 Signaling triggered by glucose limitation. Remarkably therefore, the TFEB NES integrates carbon (glucose) and nitrogen (amino acid) availability by controlling TFEB flux through a Nuclear import-Export cycle.
Jørgen Kjems - One of the best experts on this subject based on the ideXlab platform.
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CRM1 mediates the Export of ADAR1 through a Nuclear Export Signal within the Z-DNA binding domain.
Molecular and cellular biology, 2001Co-Authors: Hanne Poulsen, Jakob Nilsson, Christian Kroun Damgaard, Jan Egebjerg, Jørgen KjemsAbstract:RNA editing of specific residues by adenosine deamination is a Nuclear process catalyzed by adenosine deaminases acting on RNA (ADAR). Different promoters in the ADAR1 gene give rise to two forms of the protein: a constitutive promoter expresses a transcript encoding (c)ADAR1, and an interferon-induced promoter expresses a transcript encoding an N-terminally extended form, (i)ADAR1. Here we show that (c)ADAR1 is primarily Nuclear whereas (i)ADAR1 encompasses a functional Nuclear Export Signal in the N-terminal part and is a nucleocytoplasmic shuttle protein. Mutation of the Nuclear Export Signal or treatment with the CRM1-specific drug leptomycin B induces Nuclear accumulation of (i)ADAR1 fused to the green fluorescent protein and increases the Nuclear editing activity. In concurrence, CRM1 and RanGTP interact specifically with the (i)ADAR1 Nuclear Export Signal to form a tripartite Export complex in vitro. Furthermore, our data imply that Nuclear import of (i)ADAR1 is mediated by at least two Nuclear localization sequences. These results suggest that the Nuclear editing activity of (i)ADAR1 is modulated by Nuclear Export.
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The Specificity of the CRM1-Rev Nuclear Export Signal Interaction Is Mediated by RanGTP*
The Journal of biological chemistry, 1998Co-Authors: Peter Askjaer, Jakob Nilsson, Torben Heick Jensen, Ludwig Englmeier, Jørgen KjemsAbstract:Nuclear Export of intron-containing human immunodeficiency virus type 1 (HIV-1) RNA is mediated by the viral Rev protein that contains both an RNA binding domain specific for the viral Rev response element (RRE) and a Nuclear Export Signal (NES). The cellular CRM1 (Exportin1) protein functions as a Nuclear Export receptor for proteins carrying a Rev-like NES in a process that also requires the GTP bound form of the Ran GTPase. Using purified recombinant factors, we show by co-precipitation, gel mobility shift and protein footprinting assays that full-length Rev protein interacts directly with CRM1 in vitro independently of both the integrity of the characteristic leucine residues of the NES and the presence of the cytotoxin leptomycin B (LMB). Addition of RanGTP induces the formation of an RRE-Rev-CRM1-RanGTP complex that is sensitive to LMB, NES mutations, and Ran being charged with GTP. Within this complex, CRM1 is readily cross-linked to Cys89 near the NES of Rev. By protein footprinting, we demonstrate that the NES of Rev and two regions in CRM1 become inaccessible to endoproteinases upon binding suggesting that these regions are involved in protein-protein interactions. Our data are consistent with a model in which CRM1 is the Nuclear Export receptor for the Rev-RRE ribonucleoprotein complex and that RanGTP binds to a preformed Rev-CRM1 complex and specifies a functional interaction with the NES.
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HIV-1 rev Nuclear Export Signal binding peptides isolated by phage display.
Journal of molecular biology, 1998Co-Authors: Allan Leck Jensen, Torben Heick Jensen, Jørgen KjemsAbstract:The human immunodeficiency virus type 1 (HIV-1) Rev protein is absolutely essential in the viral replication cycle, where it induces the production of viral structural proteins. Rev functions in part by inducing the Nuclear Export of incompletely spliced mRNA species specified by the presence of an RNA element, the Rev response element (RRE). Several proteins implicated in RNA processing and nucleo-cytoplasmic transport have been shown to interact with Rev, however, their exact roles remain unknown. To map potential protein recognition sites within the Rev structure, we have screened a phage library, displaying random 15-mer peptides, and isolated clones exhibiting similar sequences that specifically interact with Rev. The binding sites on Rev of the corresponding synthetic peptides were characterised by protein footprinting, involving partial proteolysis of radioactively end-labelled Rev protein. Two of the peptides produced a significant footprint within the Nuclear Export Signal of Rev, raising the possibility that they mimic the binding of cellular protein factors implicated in Nuclear Export.
