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Caspase 8 inhibits programmed necrosis by processing CYLD
Open accessAbstract
Caspase 8 initiates apoptosis downstream of TNF death receptors by undergoing autocleavage and processing the executioner caspase 3 (ref. 1). However, the dominant function of caspase 8 is to transmit a pro-survival signal that suppresses programmed necrosis (or necroptosis) mediated by RIPK1 and RIPK3 (refs 2-6) during embryogenesis and haematopoiesis(7-9). Suppression of necrotic cell death by caspase 8 requires its catalytic activity but not the autocleavage essential for apoptosis(10); however, the key substrate processed by caspase 8 to block necrosis has been elusive. A key substrate must meet three criteria: it must be essential for programmed necrosis; it must be cleaved by caspase 8 in situations where caspase 8 is blocking necrosis; and mutation of the caspase 8 processing site on the substrate should convert a pro-survival response to necrotic death without the need for caspase 8 inhibition. We now identify CYLD as a substrate for caspase 8 that satisfies these criteria. Following TNF stimulation, caspase 8 cleaves CYLD to generate a survival signal. In contrast, loss of caspase 8 prevented CYLD degradation, resulting in necrotic death. A CYLD substitution mutation at Asp 215 that cannot be cleaved by caspase 8 switches cell survival to necrotic cell death in response to TNF.
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“Accordingly, necroptosis relies on the deubiquitinating activity of CYLD [338], which is also a proteolytic target of CASP8 [494–496].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [496]
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Cites
A gene atlas of the mouse and human protein-encoding transcriptomes
Su, A. I., Wiltshire, T., Batalov, S., Lapp, H., Ching, K. A., Block, D., Zhang, J., Soden, R., Hayakawa, M., Kreiman, G., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400782101 · Cited by 3,475
Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury
Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G. D., Mitchison, T. J., Moskowitz, M. A., & Yuan, J. (2005) · Nature Chemical Biology · doi:10.1038/nchembio711 · Cited by 3,068
Java Treeview—extensible visualization of microarray data
Saldanha, A. J. (2004) · Bioinformatics · doi:10.1093/bioinformatics/bth349 · Cited by 2,991
Cho, Y., Challa, S., Moquin, D., Genga, R., Ray, T. D., Guildford, M., & Chan, F. K.-M. (2009) · Cell · doi:10.1016/j.cell.2009.05.037 · Cited by 2,435
Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α
He, S., Wang, L., Miao, L., Wang, T., Du, F., Zhao, L., & Wang, X. (2009) · Cell · doi:10.1016/j.cell.2009.05.021 · Cited by 2,214
Identification of RIP1 kinase as a specific cellular target of necrostatins
Degterev, A., Hitomi, J., Germscheid, M., Ch'en, I. L., Korkina, O., Teng, X., Abbott, D., Cuny, G. D., Yuan, C., Wagner, G., et al. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.83 · Cited by 2,059
Holler, N., Zaru, R., Micheau, O., Thome, M., Attinger, A., Valitutti, S., Bodmer, J.-L., Schneider, P., Seed, B., & Tschopp, J. (2000) · Nature Immunology · doi:10.1038/82732 · Cited by 1,987
RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis
Zhang, D.-W., Shao, J., Lin, J., Zhang, N., Lu, B.-J., Lin, S.-C., Dong, M.-Q., & Han, J. (2009) · Science · doi:10.1126/science.1172308 · Cited by 1,931
TNF-α Induces Two Distinct Caspase-8 Activation Pathways
Wang, L., Du, F., & Wang, X. (2008) · Cell · doi:10.1016/j.cell.2008.03.036 · Cited by 1,398
Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis
Oberst, A., Dillon, C. P., Weinlich, R., McCormick, L. L., Fitzgerald, P., Pop, C., Hakem, R., Salvesen, G. S., & Green, D. R. (2011) · Nature · doi:10.1038/nature09852 · Cited by 1,278 · cited 1×
“Stable knockdown: L929 cells were transduced with pSUPERretro-puromycin encoding scrambled or RIPK3 targeting short hairpins as described previously 7 .”
Self-citationEa, C.-K., Deng, L., Xia, Z.-P., Pineda, G., & Chen, Z. J. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.026 · Cited by 1,026
Hitomi, J., Christofferson, D. E., Ng, A., Yao, J., Degterev, A., Xavier, R. J., & Yuan, J. (2008) · Cell · doi:10.1016/j.cell.2008.10.044 · Cited by 989
Self-citationSensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-κB activation
Wu, C.-J., Conze, D. B., Li, T., Srinivasula, S. M., & Ashwell, J. D. (2006) · Nature Cell Biology · doi:10.1038/ncb1384 · Cited by 619
Wolf, B. B., Schüler, M., Echeverri, F., & Green, D. R. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.43.30651 · Cited by 487
Self-citationCyld Inhibits Tumor Cell Proliferation by Blocking Bcl-3-Dependent NF-κB Signaling
Massoumi, R., Masoumi, K. C., Hennecke, K., Pfeifer, A., & Fässler, R. (2006) · Cell · doi:10.1016/j.cell.2006.03.041 · Cited by 480
Self-citationChan, F. K.-M., Shisler, J. L., Bixby, J. G., Felices, M., Zheng, L., APPEL, M. C., Orenstein, J. O., Moss, B., & Lenardo, M. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305633200 · Cited by 463
Functional complementation between FADD and RIP1 in embryos and lymphocytes
Zhang, H., Zhou, X., McQuade, T. J., Li, J., Chan, F. K.-M., & Zhang, J. (2011) · Nature · doi:10.1038/nature09878 · Cited by 428
Mitochondrial cell death effectors
Brenner, D., & Mak, T. W. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.09.004 · Cited by 414
The tumour suppressor CYLD is a negative regulator of RIG‐I‐mediated antiviral response
Friedman, C. S., O’Donnell, M. A., Legarda, D., Ng, A., Cardenas, W. B., Yount, J. S., Moran, T. M., Basler, C. F., Komuro, A., Horvath, C. M., et al. (2008) · EMBO Reports · doi:10.1038/embor.2008.136 · Cited by 334
Self-citationUbiquitination of RIP1 Regulates an NF-κB-Independent Cell-Death Switch in TNF Signaling
O'Donnell, M. A., Legarda-Addison, D., Skountzos, P., Yeh, W. C., & Ting, A. T. (2007) · Current Biology · doi:10.1016/j.cub.2007.01.027 · Cited by 310
Self-citationMechanisms of necroptosis in T cells
Ch’en, I. L., Tsau, J., Molkentin, J. D., Komatsu, M., & Hedrick, S. Μ. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20110251 · Cited by 234
Regulation of Early Wave of Germ Cell Apoptosis and Spermatogenesis by Deubiquitinating Enzyme CYLD
Wright, A., Reiley, W. W., Chang, M., Jin, W., Lee, A. J., Zhang, M., & Sun, S. (2007) · Developmental Cell · doi:10.1016/j.devcel.2007.09.007 · Cited by 212
Brouckaert, G., Kalai, M., Krysko, D. V., Saelens, X., Vercammen, D., Ndlovu, ’. N., Haegeman, G., D'Herde, K. G. M. A., & Vandenabeele, P. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e03-09-0668 · Cited by 209
Peter, M. E. (2011) · Nature · doi:10.1038/471310a · Cited by 191
Li, M. O., & Beg, A. A. (2000) · Journal of Virology · doi:10.1128/jvi.74.16.7470-7477.2000 · Cited by 146
Rapid, noninflammatory and PS-dependent phagocytic clearance of necrotic cells
Hirt, U. A., & Leist, M. (2003) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401286 · Cited by 138
Kang, T., Oh, G., Scandella, E., Bolinger, B., Ludewig, B., Kovalenko, A., & Wallach, D. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.4.2522 · Cited by 138
NEMO/IKKγ regulates an early NF-κB-independent cell-death checkpoint during TNF signaling
Legarda, D., Hase, H., O’Donnell, M. A., & Ting, A. T. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.41 · Cited by 111
Self-citationWaring, P., Lambert, D., Sjaarda, A., Hurne, A. M., & Beaver, J. (1999) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400540 · Cited by 54
Apoptosis and non-inflammatory phagocytosis can be induced by mitochondrial damage without caspases
van Delft, M. F., Smith, D. P., Lahoud, M. H., Huang, D. C. S., & Adams, J. M. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.166 · Cited by 50
RIP1 comes back to life as a cell death regulator in TNFR1 signaling
O’Donnell, M. A., & Ting, A. T. (2011) · FEBS Journal · doi:10.1111/j.1742-4658.2011.08016.x · Cited by 47
Self-citationChronicles of a death foretold: Dual sequential cell death checkpoints in TNF signaling
O’Donnell, M. A., & Ting, A. T. (2010) · Cell Cycle · doi:10.4161/cc.9.6.10982 · Cited by 32
Self-citationEssential role for IKKγ/NEMO in TCR‐induced IL‐2 expression in Jurkat T cells
He, K., & Ting, A. T. (2003) · European Journal of Immunology · doi:10.1002/eji.200323650 · Cited by 20
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Necroptosis and its role in inflammation
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Kaczmarek, A., Vandenabeele, P., & Krysko, D. V. (2013) · Immunity · doi:10.1016/j.immuni.2013.02.003 · Cited by 1,411
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Cai, Z., Jitkaew, S., Zhao, J., Chiang, H.-C., Choksi, S., Liu, J., Ward, Y., Wu, L.-G., & Liu, Z.-G. (2014) · Nature Cell Biology · doi:10.1038/ncb2883 · Cited by 1,322
Metadata
- Authors
- O’Donnell, M. A., Perez-Jimenez, E., Oberst, A., Ng, A., Massoumi, R., Xavier, R., Green, D. R., & Ting, A. T.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- St. Jude Children's Research Hospital (US)
- Harvard University (US)
- Lund University (SE)
- Corresponding author
- O’Donnell, Marie Anne
- Ting, Adrian T.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2011-10-30
- Volume
- 13
- Issue
- 12
- Pages
- 1437-1442
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC3229661
- OpenAlex
- W2091802222
- Cited by
- 494
- References
- 33
- Citations by year
- 2026: 23 · 2025: 27 · 2024: 30 · 2023: 25 · 2022: 23 · 2021: 33 · 2020: 28 · 2019: 36 · 2018: 22 · 2017: 29 · 2016: 48 · 2015: 34 · 2014: 61 · 2013: 39 · 2012: 31
- FWCI
- 17.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM052735)
- National Institute of Allergy and Infectious Diseases (R01AI044828, AI052417, R56AI052417, R01AI052417, AI44828, R37AI044828)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- caspase-8, CYLD, necroptosis, RIPK1, RIPK3, TNF signaling, cell survival signaling, embryonic development, hematopoiesis
- MeSH terms
- Deubiquitinating Enzyme CYLD, Animals, Cell Survival, Cells, Cultured, Embryo, Mammalian, Female, Fibroblasts, Humans, Necrosis, Protein Processing, Post-Translational, Signal Transduction, Jurkat Cells, Tumor Suppressor Proteins, Mice, Caspase 8, HEK293 Cells
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