TRAF2 and RIPK1 redundantly mediate classical NFκB signaling by TNFR1 and CD95-type death receptors
Abstract This study suggests a modified model of TNFR1-induced complex I-mediated NFκB signaling. Evaluation of a panel of five tumor cell lines (HCT116-PIK3CAmut, SK-MEL-23, HeLa-RIPK3, HT29, D10) with TRAF2 knockout revealed in two cell lines (HT29, HeLa-RIPK3) a sensitizing effect for death recep...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07325-x |
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| author | Jennifer Wagner David Vredevoogd Xin Yu Dong Lu Daniel S. Peeper Heike M. Hermanns Jin Wang Harald Wajant Daniela Siegmund |
| author_facet | Jennifer Wagner David Vredevoogd Xin Yu Dong Lu Daniel S. Peeper Heike M. Hermanns Jin Wang Harald Wajant Daniela Siegmund |
| author_sort | Jennifer Wagner |
| collection | DOAJ |
| description | Abstract This study suggests a modified model of TNFR1-induced complex I-mediated NFκB signaling. Evaluation of a panel of five tumor cell lines (HCT116-PIK3CAmut, SK-MEL-23, HeLa-RIPK3, HT29, D10) with TRAF2 knockout revealed in two cell lines (HT29, HeLa-RIPK3) a sensitizing effect for death receptor-induced necroptosis and in one cell line (D10) a mild sensitization for TNFR1-induced apoptosis. TRAF2 deficiency inhibited death receptor-induced classical NFκB-mediated production of IL-8 only in a subset of cell lines and only partly. TRAF5, furthermore, failed to improve DR-induced NFκB signaling in HCT116-PIK3CAmut and HCT116-PIK3CAmut-TRAF2KO cells. These findings argue for a non-obligatory role of TRAF2 in death receptor-induced classical NFκB signaling. Similar as in TRAF2-deficient cells, TNF- and CD95L-induced NFκB signaling was found to be only poorly affected in RIPK1KO cells and in cells treated with the RIPK1-specific PROTAC LD4172. Intriguingly, however, death receptor-induced NFκB signaling was completely inhibited in HCT116-PIK3CAmut cells double deficient for TRAF2 and RIPK1 and in TRAF2-deficient cells treated with LD4172. Moreover, with exception of recruitment of TRADD, acting upstream to TRAF2 and parallel to RIPK1, TNFR1 signaling complex formation was abrogated in TRAF2-RIPK1 DKO cells. Based on our findings, two distinguishable types of TNFR1-interacting complexes promote TNF-induced NFκB signaling: First, a TRADD-TRAF2/cIAP utilizing complex Ia which becomes evident in RIPK1-deficient cells. Second, a non-modified RIPK1 utilizing complex Ib which acts in TRADD- or TRAF2-deficient cells. Complex Ia and Ib may furthermore interact and cooperate to ubiquitinate RIPK1 resulting in a modified complex Ia/b preventing complex Ia and Ib to convert to the established TNFR1-induced cytotoxic complexes IIa and IIb. |
| format | Article |
| id | doaj-art-b17dfd3c4e3d4eab8954cf842c545597 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death and Disease |
| spelling | doaj-art-b17dfd3c4e3d4eab8954cf842c5455972025-01-26T12:54:40ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111410.1038/s41419-024-07325-xTRAF2 and RIPK1 redundantly mediate classical NFκB signaling by TNFR1 and CD95-type death receptorsJennifer Wagner0David Vredevoogd1Xin Yu2Dong Lu3Daniel S. Peeper4Heike M. Hermanns5Jin Wang6Harald Wajant7Daniela Siegmund8Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Auvera Haus Grombühlstraße 12Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121The Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineThe Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineDivision of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, Auvera Haus Grombühlstraße 12The Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineDivision of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Auvera Haus Grombühlstraße 12Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Auvera Haus Grombühlstraße 12Abstract This study suggests a modified model of TNFR1-induced complex I-mediated NFκB signaling. Evaluation of a panel of five tumor cell lines (HCT116-PIK3CAmut, SK-MEL-23, HeLa-RIPK3, HT29, D10) with TRAF2 knockout revealed in two cell lines (HT29, HeLa-RIPK3) a sensitizing effect for death receptor-induced necroptosis and in one cell line (D10) a mild sensitization for TNFR1-induced apoptosis. TRAF2 deficiency inhibited death receptor-induced classical NFκB-mediated production of IL-8 only in a subset of cell lines and only partly. TRAF5, furthermore, failed to improve DR-induced NFκB signaling in HCT116-PIK3CAmut and HCT116-PIK3CAmut-TRAF2KO cells. These findings argue for a non-obligatory role of TRAF2 in death receptor-induced classical NFκB signaling. Similar as in TRAF2-deficient cells, TNF- and CD95L-induced NFκB signaling was found to be only poorly affected in RIPK1KO cells and in cells treated with the RIPK1-specific PROTAC LD4172. Intriguingly, however, death receptor-induced NFκB signaling was completely inhibited in HCT116-PIK3CAmut cells double deficient for TRAF2 and RIPK1 and in TRAF2-deficient cells treated with LD4172. Moreover, with exception of recruitment of TRADD, acting upstream to TRAF2 and parallel to RIPK1, TNFR1 signaling complex formation was abrogated in TRAF2-RIPK1 DKO cells. Based on our findings, two distinguishable types of TNFR1-interacting complexes promote TNF-induced NFκB signaling: First, a TRADD-TRAF2/cIAP utilizing complex Ia which becomes evident in RIPK1-deficient cells. Second, a non-modified RIPK1 utilizing complex Ib which acts in TRADD- or TRAF2-deficient cells. Complex Ia and Ib may furthermore interact and cooperate to ubiquitinate RIPK1 resulting in a modified complex Ia/b preventing complex Ia and Ib to convert to the established TNFR1-induced cytotoxic complexes IIa and IIb.https://doi.org/10.1038/s41419-024-07325-x |
| spellingShingle | Jennifer Wagner David Vredevoogd Xin Yu Dong Lu Daniel S. Peeper Heike M. Hermanns Jin Wang Harald Wajant Daniela Siegmund TRAF2 and RIPK1 redundantly mediate classical NFκB signaling by TNFR1 and CD95-type death receptors Cell Death and Disease |
| title | TRAF2 and RIPK1 redundantly mediate classical NFκB signaling by TNFR1 and CD95-type death receptors |
| title_full | TRAF2 and RIPK1 redundantly mediate classical NFκB signaling by TNFR1 and CD95-type death receptors |
| title_fullStr | TRAF2 and RIPK1 redundantly mediate classical NFκB signaling by TNFR1 and CD95-type death receptors |
| title_full_unstemmed | TRAF2 and RIPK1 redundantly mediate classical NFκB signaling by TNFR1 and CD95-type death receptors |
| title_short | TRAF2 and RIPK1 redundantly mediate classical NFκB signaling by TNFR1 and CD95-type death receptors |
| title_sort | traf2 and ripk1 redundantly mediate classical nfκb signaling by tnfr1 and cd95 type death receptors |
| url | https://doi.org/10.1038/s41419-024-07325-x |
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