RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation
TNF is a proinflammatory cytokine that is critical for the coordination of tissue homeostasis. RIPK1 and TRADD are the main participants in the transduction of TNF signaling. However, data on the cell fate-controlling functions of both molecules are quite controversial. Here, we address the function...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/22/12459 |
| _version_ | 1797510023513899008 |
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| author | Maria Feoktistova Roman Makarov Amir S. Yazdi Diana Panayotova-Dimitrova |
| author_facet | Maria Feoktistova Roman Makarov Amir S. Yazdi Diana Panayotova-Dimitrova |
| author_sort | Maria Feoktistova |
| collection | DOAJ |
| description | TNF is a proinflammatory cytokine that is critical for the coordination of tissue homeostasis. RIPK1 and TRADD are the main participants in the transduction of TNF signaling. However, data on the cell fate-controlling functions of both molecules are quite controversial. Here, we address the functions of RIPK1 and TRADD in TNF signaling by generating RIPK1- or TRADD-deficient human cell lines. We demonstrate that RIPK1 is relevant for TNF-induced apoptosis and necroptosis in conditions with depleted IAPs. In addition, TRADD is dispensable for necroptosis but required for apoptosis. We reveal a new possible function of TRADD as a negative regulator of NIK stabilization and subsequent ripoptosome formation. Furthermore, we show that RIPK1 and TRADD do not appear to be essential for the activation of MAPK signaling. Moreover, partially repressing NF-κB activation in both RIPK1 and TRADD KO cells does not result in sensitization to TNF alone due to the absence of NIK stabilization. Importantly, we demonstrate that RIPK1 is essential for preventing TRADD from undergoing TNF-induced ubiquitination and degradation. Taken together, our findings provide further insights into the specific functions of RIPK1 and TRADD in the regulation of TNF-dependent signaling, which controls the balance between cell death and survival. |
| first_indexed | 2024-03-10T05:26:03Z |
| format | Article |
| id | doaj.art-d1ee5071d4d7482699dbbb83d6a31fe9 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T05:26:03Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d1ee5071d4d7482699dbbb83d6a31fe92023-11-22T23:42:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122221245910.3390/ijms222212459RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome FormationMaria Feoktistova0Roman Makarov1Amir S. Yazdi2Diana Panayotova-Dimitrova3Department of Dermatology and Allergology, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, GermanyDepartment of Dermatology and Allergology, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, GermanyDepartment of Dermatology and Allergology, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, GermanyDepartment of Dermatology and Allergology, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, GermanyTNF is a proinflammatory cytokine that is critical for the coordination of tissue homeostasis. RIPK1 and TRADD are the main participants in the transduction of TNF signaling. However, data on the cell fate-controlling functions of both molecules are quite controversial. Here, we address the functions of RIPK1 and TRADD in TNF signaling by generating RIPK1- or TRADD-deficient human cell lines. We demonstrate that RIPK1 is relevant for TNF-induced apoptosis and necroptosis in conditions with depleted IAPs. In addition, TRADD is dispensable for necroptosis but required for apoptosis. We reveal a new possible function of TRADD as a negative regulator of NIK stabilization and subsequent ripoptosome formation. Furthermore, we show that RIPK1 and TRADD do not appear to be essential for the activation of MAPK signaling. Moreover, partially repressing NF-κB activation in both RIPK1 and TRADD KO cells does not result in sensitization to TNF alone due to the absence of NIK stabilization. Importantly, we demonstrate that RIPK1 is essential for preventing TRADD from undergoing TNF-induced ubiquitination and degradation. Taken together, our findings provide further insights into the specific functions of RIPK1 and TRADD in the regulation of TNF-dependent signaling, which controls the balance between cell death and survival.https://www.mdpi.com/1422-0067/22/22/12459TNF signalingNF-κBapoptosisnecroptosisripoptosomeNIK |
| spellingShingle | Maria Feoktistova Roman Makarov Amir S. Yazdi Diana Panayotova-Dimitrova RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation International Journal of Molecular Sciences TNF signaling NF-κB apoptosis necroptosis ripoptosome NIK |
| title | RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation |
| title_full | RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation |
| title_fullStr | RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation |
| title_full_unstemmed | RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation |
| title_short | RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation |
| title_sort | ripk1 and tradd regulate tnf induced signaling and ripoptosome formation |
| topic | TNF signaling NF-κB apoptosis necroptosis ripoptosome NIK |
| url | https://www.mdpi.com/1422-0067/22/22/12459 |
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