XPO1E571K Mutation Modifies Exportin 1 Localisation and Interactome in B-Cell Lymphoma

Miloudi, Hadjer; Bohers, Élodie; Guilhot, François; Taly, Antoine; Gibouin, Vincent Cabaud; Viailly, Pierre‐Julien; Jego, Gaëtan; Grumolato, Luca; Jardin, Fabrice; Sola, Brigitte

doi:10.3390/cancers12102829

Cited by 15 publications

(31 citation statements)

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“…1B,C). We subsequently performed a coIP analysis between PACS‐1 and XPO1, an essential protein that binds the NES of proteins for nuclear export [30–33]. Cotransfection of PACS‐1‐WT‐FLAG and XPO1‐GFP in HEK293T cells resulted in the pulldown of XPO1‐GFP upon FLAG immunoprecipitation (Fig.…”

Section: Resultsmentioning

confidence: 99%

PACS‐1 contains distinct motifs for nuclear‐cytoplasmic transport and interacts with the RNA‐binding protein PTBP1 in the nucleus and cytosol

et al. 2021

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Phosphofurin acidic cluster sorting protein 1 (PACS‐1) is canonically a cytosolic trafficking protein, yet recent reports have described nuclear roles for PACS‐1. Herein, we sought to define the nuclear transport mechanism of PACS‐1. We demonstrate that PACS‐1 nucleocytoplasmic trafficking is dependent on its interaction with the nuclear transport receptors importin alpha 5 and exportin 1. PACS‐1 nuclear entry and exit are defined by a nuclear localization signal (NLS, residues 311‐318) and nuclear export signal (NES3, residues 366‐375). Mutation of the PACS‐1 NLS and NES3 altered the localization of a complex formed between PACS‐1 and an RNA‐binding protein, polypyrimidine tract‐binding protein 1. Overall, we identify the nuclear localization mechanism of PACS‐1 and highlight a potential role for PACS‐1 in RNA‐binding protein trafficking.

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Section: Resultsmentioning

confidence: 99%

PACS‐1 contains distinct motifs for nuclear‐cytoplasmic transport and interacts with the RNA‐binding protein PTBP1 in the nucleus and cytosol

et al. 2021

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“…Chromosomal region maintenance 1 (CRM1) is the other name of Exportin-1 (XPO1) which is encoded by XPO1 gene ( Miloudi et al, 2020 ). It has 24 HEAT repeats which form ring like structure and the hydrophobic pocket recognizes the Nuclear localization signal (NES) to transport various cargos ( Dong et al, 2009 ).…”

Section: Resultsmentioning

confidence: 99%

Decoding nonspecific interactions between human nuclear transport proteins: A computational study

Rathod

2021

Preprint

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The nuclear protein transport between the nucleus and cytosol can be considered a core process of cell regulation. Specially designed proteins in nature such as importins, exportins, and some other transporters facilitate this transport in the cell and control the cellular processes. Prior to cargo transports, the transport proteins first recognize the Nuclear localization signals (NLSs) and Nuclear export signals (NESs) of cargo proteins. NLSs and NESs are short peptides that have specific residues which help to locate them on the groove of transport proteins. However, this transport through the Nuclear pore complexes (NPCs) is not possible without the energy supplying protein, RanGTP (RAs-related nuclear protein guanosine-5-triphosphate). In addition to this, transport proteins bind with other similar protein subunits along with RanGTP to transport cargos. Hence, protein-protein binding is a vital step for the cargo movement. Here, I investigated possible bindings between 12 human nuclear transport proteins using protein-protein docking algorithm. Furthermore, the binding energy of docked complexes have been calculated and compared with the experimentally resolved complexes. Among total 78 possible complexes (12 homodimers and 66 Heterodimers), IPO13-IPO13 and KPNA6-TNPO3 were found to have the highest stability. Another complexes such as IPO4-IPO5, IPO4-IPO9, IPO9-IPO13, IPO9-KPNA6, IPO13-KPNA6, and IPO13-XPO5 have the binding energy greater than the -600 kJ/mol which indicates the stable complex formation.

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“…The proto-oncogene serine/threonine-protein kinase PIM1 (Case 16 and 17) and transmembrane protein NOTCH2 (Case 8) gene aberrations are also characteristic for DLBCL (COSMIC). XPO1 (encoding exportin protein) involvement (Case 16) was demonstrated in primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) [ 26 ]. On the contrary, the mutation of the JAK2 gene best known as a driver in myeloproliferative neoplasias [ 27 ] presented with the alteration c.1177C > G; p.Leu393Val (Case 15) and was rather considered non-pathogenic SNP according to NCBI dsSNP search results.…”

Section: Discussionmentioning

confidence: 99%

Cell-Free Total Nucleic Acid-Based Genotyping of Aggressive Lymphoma: Comprehensive Analysis of Gene Fusions and Nucleotide Variants by Next-Generation Sequencing

Mokánszki

Bicskó

Gergely

et al. 2021

Cancers

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Chromosomal translocations and pathogenic nucleotide variants both gained special clinical importance in lymphoma diagnostics. Non-invasive genotyping from peripheral blood (PB) circulating free nucleic acid has been effectively used to demonstrate cancer-related nucleotide variants, while gene fusions were not covered in the past. Our prospective study aimed to isolate and quantify PB cell-free total nucleic acid (cfTNA) from patients diagnosed with aggressive lymphoma and to compare with tumor-derived RNA (tdRNA) from the tissue sample of the same patients for both gene fusion and nucleotide variant testing. Matched samples from 24 patients were analyzed by next-generation sequencing following anchored multiplexed polymerase chain reaction (AMP) for 125 gene regions. Eight different gene fusions, including the classical BCL2, BCL6, and MYC genes, were detected in the corresponding tissue biopsy and cfTNA specimens with generally good agreement. Synchronous BCL2 and MYC translocations in double-hit high-grade B-cell lymphomas were obvious from cfTNA. Besides, mutations of 29 commonly affected genes, such as BCL2, MYD88, NOTCH2, EZH2, and CD79B, could be identified in matched cfTNA, and previously described pathogenic variants were detected in 16/24 cases (66.7%). In 3/24 cases (12.5%), only the PB sample was informative. Our prospective study demonstrates a non-invasive approach to identify frequent gene fusions and variants in aggressive lymphomas. cfTNA was found to be a high-value representative reflecting the complexity of the lymphoma aberration landscape.

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XPO1E571K Mutation Modifies Exportin 1 Localisation and Interactome in B-Cell Lymphoma

Cited by 15 publications

References 50 publications

PACS‐1 contains distinct motifs for nuclear‐cytoplasmic transport and interacts with the RNA‐binding protein PTBP1 in the nucleus and cytosol

PACS‐1 contains distinct motifs for nuclear‐cytoplasmic transport and interacts with the RNA‐binding protein PTBP1 in the nucleus and cytosol

Decoding nonspecific interactions between human nuclear transport proteins: A computational study

Cell-Free Total Nucleic Acid-Based Genotyping of Aggressive Lymphoma: Comprehensive Analysis of Gene Fusions and Nucleotide Variants by Next-Generation Sequencing

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