Cutting Edge: RIP1 Kinase Activity Is Dispensable for Normal Development but Is a Key Regulator of Inflammation in SHARPIN-Deficient Mice
Open accessAbstract
RIP1 (RIPK1) kinase is a key regulator of TNF-induced NF-κB activation, apoptosis, and necroptosis through its kinase and scaffolding activities. Dissecting the balance of RIP1 kinase activity and scaffolding function in vivo during development and TNF-dependent inflammation has been hampered by the perinatal lethality of RIP1-deficient mice. In this study, we generated RIP1 kinase–dead (Ripk1K45A) mice and showed they are viable and healthy, indicating that the kinase activity of RIP1, but not its scaffolding function, is dispensable for viability and homeostasis. After validating that the Ripk1K45A mice were specifically protected against necroptotic stimuli in vitro and in vivo, we crossed them with SHARPIN-deficient cpdm mice, which develop severe skin and multiorgan inflammation that has been hypothesized to be mediated by TNF-dependent apoptosis and/or necroptosis. Remarkably, crossing Ripk1K45A mice with the cpdm strain protected against all cpdm-related pathology. Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases.
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Pro-survival role of RIPK1 in development seems independent of both its kinase activity and RIPK3 binding, as mice expressing kinase-dead RIPK1 (e.g., RIPK1K45A) are viable and fertile.
“Intriguingly, the pro-survival role of RIPK1 in development seems to be independent of both its kinase activity and RIPK3 binding, as demonstrated by the fact that mice genetically engineered to express a kinase-dead variant of RIPK1 (e.g., RIPK1K45A) are viable and fertile [447, 499, 508].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [508]
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Cites
An endotoxin-induced serum factor that causes necrosis of tumors
Carswell, E. A., Old, L. J., Kassel, R. L., Green, S., Fiore, N., & Williamson, B. (1975) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.72.9.3666 · Cited by 4,532 · see citing works
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 · see citing works
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 · see citing works
The Death Domain Kinase RIP Mediates the TNF-Induced NF-κB Signal
Kelliher, M. A., Grimm, S., Ishida, Y., Kuo, F., Stanger, B. Z., & Leder, P. (1998) · Immunity · doi:10.1016/s1074-7613(00)80535-x · Cited by 1,102 · see citing works
Linear ubiquitination prevents inflammation and regulates immune signalling
Gerlach, B., Cordier, S. M., Schmukle, A. C., Emmerich, C. H., Rieser, E., Haas, T. L., Webb, A. I., Rickard, J. A., Anderton, H., Wong, W. W.-L., et al. (2011) · Nature · doi:10.1038/nature09816 · Cited by 940 · see citing works
Aggarwal, B. B., Gupta, S. C., & Kim, J. H. (2012) · Blood · doi:10.1182/blood-2011-04-325225 · Cited by 877 · see citing works
Activity of Protein Kinase RIPK3 Determines Whether Cells Die by Necroptosis or Apoptosis
Newton, K., Dugger, D. L., Wickliffe, K. E., Kapoor, N., de Almagro, M. C., Vucic, D., Komuves, L., Ferrando, R. E., French, D. M., Webster, J., et al. (2014) · Science · doi:10.1126/science.1249361 · Cited by 687 · see citing works
FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation
Welz, P.-S., Wullaert, A., Vlantis, K., Kondylis, V., Fernández-Majada, V., Ermolaeva, M., Kirsch, P., Sterner-Kock, A., van Loo, G., & Pasparakis, M. (2011) · Nature · doi:10.1038/nature10273 · Cited by 594 · cited 1× · see citing works
“Our data showing that RIP1 kinase activity completely rescues inflammation in the cpdm mouse add to the growing body of evidence that RIP1 kinase–dependent cell death and signaling are highly inflammatory (17).”
RIP Kinase-Dependent Necrosis Drives Lethal Systemic Inflammatory Response Syndrome
Duprez, L., Takahashi, N., Hauwermeiren, F. V., Vandendriessche, B., Goossens, V., Berghe, T. V., Declercq, W., Libert, C., Cauwels, A., & Vandenabeele, P. (2011) · Immunity · doi:10.1016/j.immuni.2011.09.020 · Cited by 591 · see citing works
The Role of the Kinases RIP1 and RIP3 in TNF-Induced Necrosis
Vandenabeele, P., Declercq, W., Van Herreweghe, F., & Vanden Berghe, T. (2010) · Science Signaling · doi:10.1126/scisignal.3115re4 · Cited by 482 · see citing works
Boisson, B., Laplantine, E., Prando, C., Giliani, S. C., Israelsson, E., Xu, Z., Abhyankar, A., Israël, L., Trevejo-Nuñez, G., Bogunovic, D., et al. (2012) · Nature Immunology · doi:10.1038/ni.2457 · Cited by 470 · see citing works
RIP1, a kinase on the crossroads of a cell's decision to live or die
Festjens, N., Berghe, T. V., Cornelis, S., & Vandenabeele, P. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402085 · Cited by 467 · see citing works
A novel role for RIP1 kinase in mediating TNFα production
Christofferson, D. E., Li, Y., Hitomi, J., Zhou, W., Upperman, C., Zhu, H., Gerber, S. A., Gygi, S. P., & Yuan, J. (2012) · Cell Death and Disease · doi:10.1038/cddis.2012.64 · Cited by 207 · see citing works
A spontaneous mutation characterized by chronic proliferative dermatitis in C57BL mice.
HogenEsch, H., Gijbels, M. J., Offerman, E. H., van der Hooft, J. J. J., van Bekkum, D. W., & ZURCHER, C. (1993) · PubMed Central · Cited by 176 · see citing works
The Emerging Role of Linear Ubiquitination in Cell Signaling
Emmerich, C. H., Schmukle, A. C., & Walczak, H. (2011) · Science Signaling · doi:10.1126/scisignal.2002187 · Cited by 79 · see citing works
Abhari, B. A., Cristofanon, S., Kappler, R., von Schweinitz, D., Humphreys, R. C., & Fulda, S. (2012) · Oncogene · doi:10.1038/onc.2012.337 · Cited by 58 · see citing works
Chan, F. K.-M., & Baehrecke, E. H. (2012) · Cell · doi:10.1016/j.cell.2011.12.020 · Cited by 40 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Self-citationNecroptosis in development, inflammation and disease
Weinlich, R., Oberst, A., Beere, H. M., & Green, D. R. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.149 · Cited by 1,016 · see citing works
Regulation of tumour necrosis factor signalling: live or let die
Brenner, D., Blaser, H., & Mak, T. W. (2015) · Nature Reviews Immunology · doi:10.1038/nri3834 · Cited by 998 · see citing works
Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases
Yuan, J., Amin, P., & Ofengeim, D. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0093-1 · Cited by 967 · see citing works
Kinase inhibitors: the road ahead
Ferguson, F. M., & Gray, N. S. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.21 · Cited by 1,009 · see citing works
Resolution of inflammation: a new therapeutic frontier
Fullerton, J. N., & Gilroy, D. W. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.39 · Cited by 937 · see citing works
Initiation and execution mechanisms of necroptosis: an overview
Grootjans, S., Vanden Berghe, T., & Vandenabeele, P. (2017) · Cell Death & Differentiation · doi:10.1038/cdd.2017.65 · Cited by 566 · see citing works
Samir, P., Malireddi, R. K. S., & Kanneganti, T.-D. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00238 · Cited by 557 · see citing works
Wang, Y., & Kanneganti, T.-D. (2021) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2021.07.038 · Cited by 545 · see citing works
Regulated cell death and inflammation: an auto-amplification loop causes organ failure
Linkermann, A., Stockwell, B. R., Krautwald, S., & Anders, H.-J. (2014) · Nature Reviews Immunology · doi:10.1038/nri3743 · Cited by 522 · see citing works
TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging
Xu, D., Jin, T., Zhu, H., Chen, H., Ofengeim, D., Zou, C., Mifflin, L., Pan, L., Amin, P., Li, W., et al. (2018) · Cell · doi:10.1016/j.cell.2018.07.041 · Cited by 461 · see citing works
RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation
Lin, J., Kumari, S., Kim, C., Van, T.-M., Wachsmuth, L., Polykratis, A., & Pasparakis, M. (2016) · Nature · doi:10.1038/nature20558 · Cited by 421 · see citing works
Necroptosis in health and diseases
Zhou, W., & Yuan, J. (2014) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2014.07.013 · Cited by 414 · see citing works
Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis
Geng, J., Ito, Y., Shi, L., Amin, P., Chu, J., Ouchida, A. T., Mookhtiar, A. K., Zhao, H., Xu, D., Shan, B., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00406-w · Cited by 325 · see citing works
RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis
Takahashi, N., Vereecke, L., Bertrand, M. J. M., Duprez, L., Berger, S. B., Divert, T., Gonçalves, A., Sze, M., Gilbert, B., Kourula, S., et al. (2014) · Nature · doi:10.1038/nature13706 · Cited by 318 · see citing works
Self-citationRIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition
Kaiser, W. J., Daley-Bauer, L. P., Thapa, R. J., Mandal, P., Berger, S. B., Huang, C., Sundararajan, A., Guo, H., Roback, L., Speck, S. H., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1401857111 · Cited by 291 · see citing works
Self-citationRojas-Rivera, D., Delvaeye, T., Roelandt, R., Nerinckx, W., Augustyns, K., Vandenabeele, P., & Bertrand, M. J. M. (2017) · Cell Death & Differentiation · doi:10.1038/cdd.2017.58 · Cited by 206 · see citing works
Poly-ubiquitination in TNFR1-mediated necroptosis
Dondelinger, Y., Darding, M., Bertrand, M. J. M., & Walczak, H. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2191-4 · Cited by 173 · see citing works
RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer
Schneider, A. T., Gautheron, J., Feoktistova, M., Roderburg, C., Loosen, S. H., Roy, S., Benz, F., Schemmer, P., Büchler, M. W., Nachbur, U., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2016.11.009 · Cited by 155 · see citing works
A20 and cell death-driven inflammation
Priem, D., van Loo, G., & Bertrand, M. J. M. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.03.001 · Cited by 139 · see citing works
Moriwaki, K., Farias Luz, N., Balaji, S., De Rosa, M. J., O’Donnell, C. L., Gough, P. J., Bertin, J., Welsh, R. M., & Chan, F. K.-M. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501662 · Cited by 116 · see citing works
Self-citationNikseresht, S., Khodagholi, F., & Ahmadiani, A. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.27055 · Cited by 58 · see citing works
RIP1 kinase activity-dependent roles in embryonic development of Fadd-deficient mice
Liu, Y., Fan, C., Zhang, Y., Yu, X., Wu, X., Zhang, X., Zhao, Q., Zhang, H., Xie, Q., Li, M., et al. (2017) · Cell Death & Differentiation · doi:10.1038/cdd.2017.78 · Cited by 42 · see citing works
Kamiya, M., Kimura, N., Umezawa, N., Hasegawa, H., & Yasuda, S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1191815 · Cited by 21 · see citing works
- Authors
- Berger, S. B., Kasparcova, V., Hoffman, S., Swift, B., Dare, L., Schaeffer, M., Capriotti, C., Cook, M., Finger, J., Hughes-Earle, A., Harris, P. A., Kaiser, W. J., Mocarski, E. S., Bertin, J., & Gough, P. J.
- Affiliations
- GlaxoSmithKline (United States) (US)
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline , Collegeville, PA 19422
- Safety Assessment, Platform Technology Sciences, GlaxoSmithKline , Collegeville, PA 19422
- Emory University (US)
- Corresponding author
- Kasparcova, Viera
- Hoffman, Sandy
- Dare, Lauren
- Schaeffer, Michelle
- Capriotti, Carol
- Cook, Michael
- Finger, Joshua
- Bertin, John
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-06
- Volume
- 192
- Issue
- 12
- Pages
- 5476-5480
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC4048763
- OpenAlex
- W1776031695
- Cited by
- 374
- References
- 17
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 27 · 2023: 20 · 2022: 25 · 2021: 34 · 2020: 38 · 2019: 41 · 2018: 36 · 2017: 45 · 2016: 39 · 2015: 22 · 2014: 19
- FWCI
- 17.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DP5OD012198)
- National Institute of Allergy and Infectious Diseases (R01AI20211, R01AI020211, R01AI118853)
- 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 › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- RIP1 kinase, RIPK1, SHARPIN, necroptosis, TNF-induced inflammation, NF-κB activation, apoptosis, perinatal lethality, inflammatory skin diseases, therapeutic target
- MeSH terms
- Animals, Carrier Proteins, Inflammation, Mice, Mutant Strains, Tumor Necrosis Factor-alpha, Apoptosis, Intracellular Signaling Peptides and Proteins, Mice, Receptor-Interacting Protein Serine-Threonine Kinases
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