Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex
Abstract Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) drives viral B cell transformation and oncogenesis. LMP1’s transforming activity depends on its C-terminal activation region 2 (CTAR2), which induces NF-κB and JNK by engaging TNF receptor-associated factor 6 (TRAF6). The mechanism o...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44455-w |
| _version_ | 1797355645563830272 |
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| author | Fabian Giehler Michael S. Ostertag Thomas Sommermann Daniel Weidl Kai R. Sterz Helmut Kutz Andreas Moosmann Stephan M. Feller Arie Geerlof Brigitte Biesinger Grzegorz M. Popowicz Johannes Kirchmair Arnd Kieser |
| author_facet | Fabian Giehler Michael S. Ostertag Thomas Sommermann Daniel Weidl Kai R. Sterz Helmut Kutz Andreas Moosmann Stephan M. Feller Arie Geerlof Brigitte Biesinger Grzegorz M. Popowicz Johannes Kirchmair Arnd Kieser |
| author_sort | Fabian Giehler |
| collection | DOAJ |
| description | Abstract Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) drives viral B cell transformation and oncogenesis. LMP1’s transforming activity depends on its C-terminal activation region 2 (CTAR2), which induces NF-κB and JNK by engaging TNF receptor-associated factor 6 (TRAF6). The mechanism of TRAF6 recruitment to LMP1 and its role in LMP1 signalling remains elusive. Here we demonstrate that TRAF6 interacts directly with a viral TRAF6 binding motif within CTAR2. Functional and NMR studies supported by molecular modeling provide insight into the architecture of the LMP1-TRAF6 complex, which differs from that of CD40-TRAF6. The direct recruitment of TRAF6 to LMP1 is essential for NF-κB activation by CTAR2 and the survival of LMP1-driven lymphoma. Disruption of the LMP1-TRAF6 complex by inhibitory peptides interferes with the survival of EBV-transformed B cells. In this work, we identify LMP1-TRAF6 as a critical virus-host interface and validate this interaction as a potential therapeutic target in EBV-associated cancer. |
| first_indexed | 2024-03-08T14:14:07Z |
| format | Article |
| id | doaj.art-6129e63ef175431f88dcfe4bca0f1328 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T14:14:07Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-6129e63ef175431f88dcfe4bca0f13282024-01-14T12:28:48ZengNature PortfolioNature Communications2041-17232024-01-0115111810.1038/s41467-023-44455-wEpstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complexFabian Giehler0Michael S. Ostertag1Thomas Sommermann2Daniel Weidl3Kai R. Sterz4Helmut Kutz5Andreas Moosmann6Stephan M. Feller7Arie Geerlof8Brigitte Biesinger9Grzegorz M. Popowicz10Johannes Kirchmair11Arnd Kieser12Research Unit Signaling and Translation, Helmholtz Center Munich - German Research Center for Environmental HealthInstitute of Structural Biology, Helmholtz Center Munich - German Research Center for Environmental HealthImmune Regulation and Cancer, Max Delbrück Center for Molecular MedicineInstitute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-NurembergResearch Unit Gene Vectors, Helmholtz Center Munich - German Research Center for Environmental HealthResearch Unit Gene Vectors, Helmholtz Center Munich - German Research Center for Environmental HealthResearch Unit Gene Vectors, Helmholtz Center Munich - German Research Center for Environmental HealthInstitute of Molecular Medicine, Martin-Luther-University Halle-WittenbergInstitute of Structural Biology, Helmholtz Center Munich - German Research Center for Environmental HealthInstitute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-NurembergInstitute of Structural Biology, Helmholtz Center Munich - German Research Center for Environmental HealthUniversität Hamburg, Department of Informatics, Center for Bioinformatics (ZBH)Research Unit Signaling and Translation, Helmholtz Center Munich - German Research Center for Environmental HealthAbstract Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) drives viral B cell transformation and oncogenesis. LMP1’s transforming activity depends on its C-terminal activation region 2 (CTAR2), which induces NF-κB and JNK by engaging TNF receptor-associated factor 6 (TRAF6). The mechanism of TRAF6 recruitment to LMP1 and its role in LMP1 signalling remains elusive. Here we demonstrate that TRAF6 interacts directly with a viral TRAF6 binding motif within CTAR2. Functional and NMR studies supported by molecular modeling provide insight into the architecture of the LMP1-TRAF6 complex, which differs from that of CD40-TRAF6. The direct recruitment of TRAF6 to LMP1 is essential for NF-κB activation by CTAR2 and the survival of LMP1-driven lymphoma. Disruption of the LMP1-TRAF6 complex by inhibitory peptides interferes with the survival of EBV-transformed B cells. In this work, we identify LMP1-TRAF6 as a critical virus-host interface and validate this interaction as a potential therapeutic target in EBV-associated cancer.https://doi.org/10.1038/s41467-023-44455-w |
| spellingShingle | Fabian Giehler Michael S. Ostertag Thomas Sommermann Daniel Weidl Kai R. Sterz Helmut Kutz Andreas Moosmann Stephan M. Feller Arie Geerlof Brigitte Biesinger Grzegorz M. Popowicz Johannes Kirchmair Arnd Kieser Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex Nature Communications |
| title | Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex |
| title_full | Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex |
| title_fullStr | Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex |
| title_full_unstemmed | Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex |
| title_short | Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex |
| title_sort | epstein barr virus driven b cell lymphoma mediated by a direct lmp1 traf6 complex |
| url | https://doi.org/10.1038/s41467-023-44455-w |
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