Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1’s Cytotoxic Potential
Summary: Tumor necrosis factor (TNF) is an inflammatory cytokine that can signal cell survival or cell death. The mechanisms that switch between these distinct outcomes remain poorly defined. Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivati...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-04-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718303991 |
| _version_ | 1818380012010602496 |
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| author | Rebecca Feltham Kunzah Jamal Tencho Tenev Gianmaria Liccardi Isabel Jaco Celia Monteiro Domingues Otto Morris Sidonie Wicky John Alessandro Annibaldi Marcella Widya Conor J. Kearney Danielle Clancy Paul R. Elliott Timo Glatter Qi Qiao Andrew J. Thompson Alexey Nesvizhskii Alexander Schmidt David Komander Hao Wu Seamus Martin Pascal Meier |
| author_facet | Rebecca Feltham Kunzah Jamal Tencho Tenev Gianmaria Liccardi Isabel Jaco Celia Monteiro Domingues Otto Morris Sidonie Wicky John Alessandro Annibaldi Marcella Widya Conor J. Kearney Danielle Clancy Paul R. Elliott Timo Glatter Qi Qiao Andrew J. Thompson Alexey Nesvizhskii Alexander Schmidt David Komander Hao Wu Seamus Martin Pascal Meier |
| author_sort | Rebecca Feltham |
| collection | DOAJ |
| description | Summary: Tumor necrosis factor (TNF) is an inflammatory cytokine that can signal cell survival or cell death. The mechanisms that switch between these distinct outcomes remain poorly defined. Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation. Although depletion of MIB2 has little effect on NF-κB activation, it sensitizes cells to RIPK1- and caspase-8-dependent cell death. We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. Disruption of MIB2-mediated ubiquitylation, either by mutation of MIB2’s E3 activity or RIPK1’s ubiquitin-acceptor lysines, sensitizes cells to RIPK1-mediated cell death. Together, our findings demonstrate that Mind Bomb E3 ubiquitin ligases can function as additional checkpoint of cytokine-induced cell death, selectively protecting cells from the cytotoxic effects of TNF. : Feltham et al. show that MIB2 directly ubiquitylates RIPK1 upon TNF stimulation, suppressing the cytotoxic potential of RIPK1 and acting as a checkpoint within the TNF signaling pathway. Keywords: MIB2, RIPK1, TNF, cell death, caspase-8, IAPs, ubiquitin |
| first_indexed | 2024-12-14T02:11:54Z |
| format | Article |
| id | doaj.art-fc7892f65de842ac9dd037eab1a8ff41 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-14T02:11:54Z |
| publishDate | 2018-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-fc7892f65de842ac9dd037eab1a8ff412022-12-21T23:20:45ZengElsevierCell Reports2211-12472018-04-01232470484Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1’s Cytotoxic PotentialRebecca Feltham0Kunzah Jamal1Tencho Tenev2Gianmaria Liccardi3Isabel Jaco4Celia Monteiro Domingues5Otto Morris6Sidonie Wicky John7Alessandro Annibaldi8Marcella Widya9Conor J. Kearney10Danielle Clancy11Paul R. Elliott12Timo Glatter13Qi Qiao14Andrew J. Thompson15Alexey Nesvizhskii16Alexander Schmidt17David Komander18Hao Wu19Seamus Martin20Pascal Meier21The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UK; Walter and Elisa Hall Institute, 1G Royal Parade, Parkville, Victoria 3052, AustraliaThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UK; AstraZeneca, IMED Oncology, Bioscience, DDR Group, Chesterford Research Park, Little Chesterford CB10 1XL, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UKMolecular Cell Biology Laboratory, Department of Genetics & The Smurfit Institute, Immunology Research Centre, Trinity College, Dublin 2, IrelandMolecular Cell Biology Laboratory, Department of Genetics & The Smurfit Institute, Immunology Research Centre, Trinity College, Dublin 2, IrelandMedical Research Council, Laboratory of Molecular Biology, Cambridge, UKProteomics Core Facility, Biocentrum of the University of Basel, Basel, Switzerland; Max Planck Institute for Terrestrial Microbiology, Karl-von-Frisch Strasse 10, 35043 Marburg, GermanyDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02115, USAThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UKDepartment of Pathology Department of Computational Medicine & Bioinformatics University of Michigan, Ann Arbor, MI, USAProteomics Core Facility, Biocentrum of the University of Basel, Basel, SwitzerlandMedical Research Council, Laboratory of Molecular Biology, Cambridge, UKDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02115, USAMolecular Cell Biology Laboratory, Department of Genetics & The Smurfit Institute, Immunology Research Centre, Trinity College, Dublin 2, IrelandThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UK; Corresponding authorSummary: Tumor necrosis factor (TNF) is an inflammatory cytokine that can signal cell survival or cell death. The mechanisms that switch between these distinct outcomes remain poorly defined. Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation. Although depletion of MIB2 has little effect on NF-κB activation, it sensitizes cells to RIPK1- and caspase-8-dependent cell death. We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. Disruption of MIB2-mediated ubiquitylation, either by mutation of MIB2’s E3 activity or RIPK1’s ubiquitin-acceptor lysines, sensitizes cells to RIPK1-mediated cell death. Together, our findings demonstrate that Mind Bomb E3 ubiquitin ligases can function as additional checkpoint of cytokine-induced cell death, selectively protecting cells from the cytotoxic effects of TNF. : Feltham et al. show that MIB2 directly ubiquitylates RIPK1 upon TNF stimulation, suppressing the cytotoxic potential of RIPK1 and acting as a checkpoint within the TNF signaling pathway. Keywords: MIB2, RIPK1, TNF, cell death, caspase-8, IAPs, ubiquitinhttp://www.sciencedirect.com/science/article/pii/S2211124718303991 |
| spellingShingle | Rebecca Feltham Kunzah Jamal Tencho Tenev Gianmaria Liccardi Isabel Jaco Celia Monteiro Domingues Otto Morris Sidonie Wicky John Alessandro Annibaldi Marcella Widya Conor J. Kearney Danielle Clancy Paul R. Elliott Timo Glatter Qi Qiao Andrew J. Thompson Alexey Nesvizhskii Alexander Schmidt David Komander Hao Wu Seamus Martin Pascal Meier Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1’s Cytotoxic Potential Cell Reports |
| title | Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1’s Cytotoxic Potential |
| title_full | Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1’s Cytotoxic Potential |
| title_fullStr | Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1’s Cytotoxic Potential |
| title_full_unstemmed | Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1’s Cytotoxic Potential |
| title_short | Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1’s Cytotoxic Potential |
| title_sort | mind bomb regulates cell death during tnf signaling by suppressing ripk1 s cytotoxic potential |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718303991 |
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