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RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis
Open accessAbstract
Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.
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“Likewise, the absence of Ripk1 from keratinocytes promotes spontaneous necroptosis and consequent cutaneous inflammation, which can be prevented by the co-deletion of Ripk3, Mlkl, or Zbp1 but not Fadd [440, 502].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [502]
In the citing paper
“Conditional knockout mouse models demonstrate the key role of RIPK1 for the preservation of intestinal and cutaneous homeostasis and survival [502, 503].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [502]
In the citing paper
“In particular, mice lacking Ripk1 in intestinal epithelial cells display increased rates of spontaneous CASP8-driven apoptosis and develop severe inflammatory lesions leading to premature death, a detrimental phenotype that can be prevented by co-deleting Fadd or (to a lesser degree) Tnfrsf1a [502].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [502]
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BackgroundInfluentialRIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation
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BackgroundMethodInfluentialSelf-citationHuman RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases
Li, Y., Führer, M., Bahrami, E., Socha, P., Klaudel‐Dreszler, M., Bouzidi, A., Liu, Y., Lehle, A. S., Magg, T., Hollizeck, S., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1813582116 · Cited by 195
“Mice with Ripk1 KO in intestinal epithelial cells develop colitis accompanied by disrupted tissue architecture and increased apoptosis (8, 11).”
BackgroundZBP1 mediates interferon-induced necroptosis
Yang, D., Liang, Y., Zhao, S., Ding, Y. P., Zhuang, Q., Shi, Q., Ai, T., Wu, S., & Han, J. (2019) · Cellular and Molecular Immunology · doi:10.1038/s41423-019-0237-x · Cited by 202
Woznicki, J. A., Saini, N., Flood, P. F., Rajaram, S., Lee, C. M., Stamou, P., Skowyra, A., Bustamante-Garrido, M., Regazzoni, K., Crawford, N., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-04151-3 · Cited by 203
“Both these processes relied, however, on FADD and RIPK1, which are not required for IFN-γ/ TNF-α-induced death of IECs (unpublished data).”
BackgroundInfluentialComplex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond Necroptosis
Wegner, K. W., Saleh, D., & Degterev, A. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.12.005 · Cited by 189
Roles of RIPK3 in necroptosis, cell signaling, and disease
Morgan, M. J., & Kim, Y. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00868-z · Cited by 197
Holding RIPK1 on the Ubiquitin Leash in TNFR1 Signaling
Peltzer, N., Darding, M., & Walczak, H. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.01.006 · Cited by 184
“However, these mice still displayed the inflammatory intestinal phenotype of Fadd, which is due to excessive RIPK3-mediated necroptosis [41,42].”
BackgroundInfluentialInhibitors Targeting RIPK1/RIPK3: Old and New Drugs
Martens, S., Hofmans, S., Declercq, W., Augustyns, K., & Vandenabeele, P. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.01.002 · Cited by 183
Necroptosis: an alternative cell death program defending against cancer
Chen, D., Yu, J., & Zhang, L. (2016) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2016.03.003 · Cited by 191
CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3
Seo, J., Lee, E.-W., Sung, H., Seong, D., Dondelinger, Y., Shin, J., Jeong, M., Lee, H.-K., Kim, J.-H., Han, S. Y., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3314 · Cited by 182
Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling
Kitur, K., Wachtel, S., Brown, A. O., Wickersham, M., Paulino, F. E., Peñaloza, H. F., Soong, G., Bueno, S. M., Parker, D., & Prince, A. S. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.07.039 · Cited by 181
“Germline mutations in RIPK1/3, caspase-8, and FADD that interrupt the normal regulation of cell death pathways lead to excessive skin inflammation (Dannappel et al., 2014), even in the absence of a potent stimulus, such as 2226 Cell Reports 16, 2219–2230, August 23, 2016 staphylococci.”
ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS–STING
Aden, K., Tran, F., Ito, G., Sheibani-Tezerji, R., Lipinski, S., Kuiper, J. W., Tschurtschenthaler, M., Saveljeva, S., Bhattacharyya, J., Häsler, R., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20171029 · Cited by 167
“Autophagy is also closely intertwined to the unfolded protein response (UPR), elicited from the endoplasmic reticulum (Adolph et al., 2013; Deuring et al., 2014; Tschurtschenthaler et al., 2017).”
BackgroundSelf-citationDara, L., Johnson, H. S., Suda, J., Win, S., Gaarde, W. A., Han, D., & Kaplowitz, N. (2015) · Hepatology · doi:10.1002/hep.27939 · Cited by 178
“Furthermore, it has been recently shown that in certain cell types, such as intestinal epithelial cells, RIPK1 paradoxically promotes cell survival, indicating the intricacies of survival and death pathways and potentially alternative and kinase independent functions for RIPK1.(16,17) The first studies showing the rol…”
BackgroundInfluentialLiu, T., Kern, J. T., Jain, U., Sonnek, N. M., Xiong, S., Simpson, K. F., VanDussen, K. L., Winkler, E. S., Haritunians, T., Malique, A., et al. (2021) · Cell Host & Microbe · doi:10.1016/j.chom.2021.04.004 · Cited by 179
Emerging insights into human health and NK cell biology from the study of NK cell deficiencies
Mace, E. M., & Orange, J. S. (2018) · Immunological Reviews · doi:10.1111/imr.12725 · Cited by 175
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
“As such, in contrast to previous findings in gut or skin (Dannappel et al., 2014; Takahashi et al., 2014), conditional deletion of Ripk1 in LPC did not cause spontaneous hepatocyte apoptosis and hepatitis.”
ResultApoptosis, Necrosis, and Necroptosis in the Gut and IntestinalHomeostasis
Negroni, A., Cucchiara, S., & Stronati, L. (2015) · Mediators of Inflammation · doi:10.1155/2015/250762 · Cited by 169
“Recent papers on knock-out mice showed kinaseindependent RIP1 functions regulating homeostasis and preventing inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis [40, 41].”
BackgroundSchwarzer, R., Laurien, L., & Pasparakis, M. (2020) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2020.02.004 · Cited by 162
Self-citationThe pathological features of regulated necrosis
Tonnus, W., Meyer, C., Paliege, A., Belavgeni, A., von Mäßenhausen, A., Bornstein, S. R., Hugo, C., Becker, J. U., & Linkermann, A. (2019) · The Journal of Pathology · doi:10.1002/path.5248 · Cited by 168
Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1
Najjar, M., Suebsuwong, C., Ray, S. S., Thapa, R. J., Maki, J. L., Nogusa, S., Shah, S., Saleh, D., Gough, P. J., Bertin, J., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.02.052 · Cited by 156
“, 2013), and necroptosis (Dannappel et al., 2014; Dillon et al., 2014; Kaiser et al., 2014; Orozco et al., 2014).”
BackgroundIntrinsic Defense Mechanisms of the Intestinal Epithelium
Ramanan, D., & Cadwell, K. (2016) · Cell Host & Microbe · doi:10.1016/j.chom.2016.03.003 · Cited by 162
“The NFκB and RipK1 pathway counteracts signals downstream of cytokines and microbes to prevent epithelial cell death and ensuing inflammation (Dannappel et al., 2014; Nenci et al., 2007; Takahashi et al., 2014).”
BackgroundProgrammed necrosis and necroptosis signalling
Feoktistova, M., & Leverkus, M. (2014) · FEBS Journal · doi:10.1111/febs.13120 · Cited by 159
Characterization of GSK′963: a structurally distinct, potent and selective inhibitor of RIP1 kinase
Berger, S., Harris, P. A., Nagilla, R., Kasparcova, V., Hoffman, S., Swift, B., Dare, L. C., Schaeffer, M. C., Capriotti, C. A., Ouellette, M. T., et al. (2015) · Cell Death Discovery · doi:10.1038/cddiscovery.2015.9 · Cited by 153
TWEAK and RIPK1 mediate a second wave of cell death during AKI
Martín‐Sánchez, D., Fontecha‐Barriuso, M., Carrasco, S., Sánchez-Niño, M. D., von Mäßenhausen, A., Linkermann, A., Cannata‐Ortiz, P., Ruiz‐Ortega, M., Egido, J., Ortíz, A., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1716578115 · Cited by 153
“However, the RIPK1 protein devoid of kinase activity appears to function as a cell death inhibitor (18, 19).”
Gut mucosal DAMPs in IBD: from mechanisms to therapeutic implications
Boyapati, R. K., Rossi, A. G., Satsangi, J., & Ho, G. (2016) · Mucosal Immunology · doi:10.1038/mi.2016.14 · Cited by 150
“RIPK1 also appears to have a kinase-independent role in regulating intestinal homeostasis where IEC-specific RIPK1 KO mice develop severe intestinal inflammation associated with IEC apoptosis.(170,171) Necrostatins such as necrostatin-1 inhibit necroptosis through inhibition of RIPK1 and have been used to investigate…”
BackgroundCell death in chronic inflammation: breaking the cycle to treat rheumatic disease
Anderton, H., Wicks, I. P., & Silke, J. (2020) · Nature Reviews Rheumatology · doi:10.1038/s41584-020-0455-8 · Cited by 150
Linear ubiquitination in immunity
Shimizu, Y., Taraborrelli, L., & Walczak, H. (2015) · Immunological Reviews · doi:10.1111/imr.12309 · Cited by 138
“Deletion of Ripk1 in the epidermal keratinocytes (Ripk1) instead leads to a skin inflammatory phenotype that is completely prevented by genetic ablation of the two known downstream components of necroptosis signaling, RIPK3 or MLKL, indicating that in this case aberrant necroptosis is causative for inflammation (79).”
BackgroundInfluentialRole of necroptosis in the pathogenesis of solid organ injury
Zhao, H., Jaffer, T., Eguchi, S., Wang, Z., Linkermann, A., & Ma, D. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.316 · Cited by 143
“Gastrointestinal tract Crohn’s and ulcerative colitis: RIPK1 was reported to regulate homeostasis and suppress inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis.(64) A study into children with inflammatory bowel disease showed that necroptosis might contribute to its progression b…”
BackgroundA20 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
Mechanisms of Pediatric Inflammatory Bowel Disease
Peloquin, J. M., Goel, G., Villablanca, E. J., & Xavier, R. J. (2016) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032414-112151 · Cited by 141
Kondylis, V., Polykratis, A., Ehlken, H., Ochoa-Callejero, L., Straub, B. K., Krishna-Subramanian, S., Van, T.-M., Curth, H.-M., Heise, N., Weih, F., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.10.001 · Cited by 131
“To further dissect the role of the kinase activity-dependent and scaffolding functions of RIPK1 in hepatocyte death, we generated mice lacking both NEMO and RIPK1 in the liver by crossing NemoFL/FL;Alfp-Cre mice with Ripk1FL/FL mice.”
Self-citationThe intestinal epithelium as guardian of gut barrier integrity
Zhang, K., Hornef, M. W., & Dupont, A. (2015) · Cellular Microbiology · doi:10.1111/cmi.12501 · Cited by 138
“The critical importance of cell death regulation even under homeostatic conditions is illustrated by the severe intestinal damage observed in animals deficient in cell death regulatory molecules (Dannappel et al., 2014, Takahashi et al., 2014).”
BackgroundThe Two Faces of Receptor Interacting Protein Kinase-1
Weinlich, R., & Green, D. R. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.11.001 · Cited by 131
“2014), conditional (Dannappel et al., 2014; Takahashi et al., 2014), or acute (Takahashi et al.”
BackgroundInfluentialThe MLKL Channel in Necroptosis Is an Octamer Formed by Tetramers in a Dyadic Process
Huang, D., Zheng, X., Wang, Z.-A., Chen, X., He, W., Zhang, Y., Xu, J.-G., Zhao, H., Shi, W., Wang, X., et al. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.00497-16 · Cited by 138
An outline of necrosome triggers
Berghe, T. V., Hassannia, B., & Vandenabeele, P. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2189-y · Cited by 134
Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes
Kaustio, M., Haapaniemi, E. M., Göös, H., Hautala, T., Park, G., Syrjänen, J., Einarsdóttir, E., Sahu, B., Kilpinen, S., Rounioja, S., et al. (2017) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2016.10.054 · Cited by 138
Interferons and the immunogenic effects of cancer therapy
Minn, A. J. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.09.007 · Cited by 130
“RIPK1-deficient keratinocytes trigger inflammation through necroptosis but not apoptosis [25].”
Background
Metadata
- Authors
- Dannappel, M., Vlantis, K., Kumari, S., Polykratis, A., Kim, C., Wachsmuth, L., Eftychi, C., Lin, J., Corona, T., Hermance, N., Zelic, M., Kirsch, P., Basic, M., Bleich, A., Kelliher, M., & Pasparakis, M.
- Affiliations
- University of Cologne (DE)
- University of Massachusetts Chan Medical School (US)
- Universität Ulm (DE)
- Medizinische Hochschule Hannover (DE)
- Corresponding author
- Pasparakis, Manolis
- ORCID
- Venue
- Nature
- Published
- 2014-08-17
- Volume
- 513
- Issue
- 7516
- Pages
- 90-94
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4206266
- OpenAlex
- W1985231277
- Cited by
- 534
- References
- 47
- Citations by year
- 2026: 21 · 2025: 33 · 2024: 46 · 2023: 36 · 2022: 56 · 2021: 47 · 2020: 47 · 2019: 49 · 2018: 44 · 2017: 33 · 2016: 59 · 2015: 49 · 2014: 14
- FWCI
- 21.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI075118, T32AI095213)
- 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
- RIPK1, necroptosis, apoptosis, epithelial homeostasis, FADD, caspase-8, RIPK3, intestinal epithelium, skin inflammation, keratinocytes, TNFR1, barrier tissues, inflammation, programmed cell death, Paneth cells, goblet cells, villous atrophy, intestinal inflammation
- MeSH terms
- Animals, Cell Survival, Epithelial Cells, Female, Homeostasis, Inflammation, Intestinal Mucosa, Intestines, Male, Necrosis, Skin, Keratinocytes, Apoptosis, Mice, Knockout, Paneth Cells, Receptors, Tumor Necrosis Factor, Type I, Mice, Caspase 8, Fas-Associated Death Domain Protein, Receptor-Interacting Protein Serine-Threonine Kinases, Myeloid Differentiation Factor 88
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