Cited by 601Cell death mechanisms and regulationInflammatory Bowel DiseaseNF-κB Signaling Pathways

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FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation

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Welz, Patrick-Simon, Wullaert, Andy, Vlantis, Katerina, Kondylis, Vangelis, Fernández-Majada, Vanesa, Ermolaeva, Maria, Kirsch, Petra, Sterner-Kock, Anja, van Loo, Geert, Pasparakis, Manolis·2011·Nature

DOI 10.1038/nature10273

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Abstract

Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). Epithelial barrier disruption is considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood. Here we show that mice with IEC-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death-receptor-induced apoptosis, spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis, prevented the development of spontaneous pathology in both the small intestine and colon of FADD(IEC-KO) mice, demonstrating that intestinal inflammation is triggered by RIP3-dependent death of FADD-deficient IECs. Epithelial-specific inhibition of CYLD, a deubiquitinase that regulates cellular necrosis, prevented colitis development in FADD(IEC-KO) but not in NEMO(IEC-KO) mice, showing that different mechanisms mediated death of colonic epithelial cells in these two models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon inflammation, whereas MYD88 deficiency and also elimination of the microbiota prevented colon inflammation, indicating that bacteria-mediated Toll-like-receptor signalling drives colitis by inducing the expression of TNF and other cytokines. However, neither CYLD, TNF or MYD88 deficiency nor elimination of the microbiota could prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing that different mechanisms drive RIP3-dependent necrosis of FADD-deficient IECs in the small and large bowel. Therefore, by inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier integrity and antibacterial defence, maintains homeostasis and prevents chronic intestinal inflammation. Collectively, these results show that mechanisms preventing RIP3-mediated epithelial cell death are critical for the maintenance of intestinal homeostasis and indicate that programmed necrosis of IECs might be implicated in the pathogenesis of inflammatory bowel disease, in which Paneth cell and barrier defects are thought to contribute to intestinal inflammation.

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Background
Understanding the Role of Connexins in Hepatocellular Carcinoma: Molecular and Prognostic Implications
Papadakos, S. P., Chatzikalil, E., Arvanitakis, K., Vakadaris, G., Stergiou, I. Ε., Koutsompina, M.-L., Argyrou, A., Lekakis, V., Konstantinidis, I., Germanidis, G. S., et al. (2024) · Cancers · doi:10.3390/cancers16081533 · Cited by 11
“Considering the role of caspase 8 in regulating apoptosis by activating downstream caspase cascades and in inhibiting necroptosis by cleaving RIPK1, Xiang et al. proved that Cx32 activates necroptosis in HCC cells via mediating the inactivation of caspase 8 [72,140,141].”
Background
METTL3 restricts RIPK1-dependent cell death via the ATF3-cFLIP axis in the intestinal epithelium
Huang, M., Wang, X., Zhang, M., Liu, Y., & Chen, Y. (2024) · Cell Regeneration · doi:10.1186/s13619-024-00197-8 · Cited by 10
“Ablation of FADD or caspase 8 in IECs leads to non-apoptotic cell death and spontaneous gut inflammation, which can be reversed by further knockout of RIPK3 (Günther et al. 2011; Welz et al. 2011).”
Background
Fungal Als proteins hijack host death effector domains to promote inflammasome signaling
Zhou, T., Solis, N. V., Marshall, M. E., Yao, Q., Pearlman, E. M., Filler, S. G., & Liu, H. (2025) · Nature Communications · doi:10.1038/s41467-025-56657-5 · Cited by 10
Hydrogen sulfide protects from acute kidney injury via attenuating inflammation activated by necroptosis in dogs
Wang, S., Liu, X., & Liu, Y. (2022) · Journal of Veterinary Science · doi:10.4142/jvs.22064 · Cited by 10
Identification of an antibody‐based immunoassay for measuring direct target binding of RIPK 1 inhibitors in cells and tissues
Finger, J. N., Brusq, J.-M. G., Campobasso, N., Cook, M. N., Deutsch, J., Haag, H., Harris, P. A., Jenkins, E. L., Joglekar, D., Lich, J. D., et al. (2017) · Pharmacology Research & Perspectives · doi:10.1002/prp2.377 · Cited by 10
“Ab3, Ab4, Ab6, and Ab7 are shown, though they do not overlap with the RIPK1 (1-324) truncated protein used in HDX-MS.”
Method
FADD: an endogenous inhibitor of RIP3-driven regulated necrosis
Galluzzi, L., Kepp, O., & Kroemer, G. (2011) · Cell Research · doi:10.1038/cr.2011.147 · Cited by 10
Epithelial NELF guards intestinal barrier function to ameliorate colitis by maintaining junctional integrity
Ou, J., Guan, X., Wang, J., Wang, T., Zhang, B., Li, R., Xu, H., Hu, X., & Guo, X.-K. (2021) · Mucosal Immunology · doi:10.1038/s41385-021-00465-9 · Cited by 10
The roles of long non-coding RNAs in the necroptotic signaling of colon cancer cells
Bozgeyi̇k, E., Bağış, H., Bozgeyik, İ., & Kocahan, S. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08441-1 · Cited by 9
Programmed Necrosis in Host Defense
Mocarski, E. S. (2023) · Current topics in microbiology and immunology · doi:10.1007/82_2023_264 · Cited by 8
Necroptosis and Its Involvement in Various Diseases
Nakano, H. (2024) · Advances in experimental medicine and biology · doi:10.1007/978-981-99-9781-7_9 · Cited by 10
Self-renewal and Differentiation of Muscle Satellite Cells Are Regulated by the Fas-associated Death Domain
Cheng, W., Wang, L., Yang, B., Zhang, R., Yao, C., He, L., Liu, Z., Du, P., Hammache, K., Wen, J., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.533448 · Cited by 10
“Recently, FADD has been shown to play a role in regulating embryogenesis, thymus development, and chronic intestinal inflammation by suppressing receptor-interacting protein (RIP)-induced necrosis (16, 17).”
Background
Role of Fas-Associated Death Domain-containing Protein (FADD) Phosphorylation in Regulating Glucose Homeostasis: from Proteomic Discovery to Physiological Validation
Yao, C., Zhuang, H., Du, P., Cheng, W., Yang, B., Guan, S., Hu, Y., Zhu, D., Christine, M. H., Shi, L., et al. (2013) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m113.029306 · Cited by 10
FADD Phosphorylation Modulates Blood Glucose Levels by Decreasing the Expression of Insulin-Degrading Enzyme.
Lin, Y., Liu, J., Chen, J., Yao, C., Yang, Y., Wang, J., Zhuang, H., & Hua, Z. (2020) · PubMed Central · doi:10.14348/molcells.2020.2198 · Cited by 9
“…a series of nonapoptotic processes regulated by its phosphorylation (Bonnet et al., 2011; Hua et al., 2003; Imtiyaz et al., 2009; Kabra et al., 2001; Lee et al., 2012; Matsuyoshi et al., 2006; Pyo et al., 2005; Shimada et al., 2006; Thomas et al., 2004; Welz et al., 2011; Yao et al., 2013; 2015).”
Background
Oral squamous carcinoma cell lysates provoke exacerbated inflammatory response in gingival fibroblasts
Sordi, M. B., Panahipour, L., & Gruber, R. (2023) · Clinical Oral Investigations · doi:10.1007/s00784-023-05107-x · Cited by 8
Regulation of Different Types of Cell Death by Noncoding RNAs: Molecular Insights and Therapeutic Implications
Kumari, R., & Banerjee, S. (2025) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00681 · Cited by 9
Functional specific roles of FADD: comparative proteomic analyses from knockout cell lines
Zhuang, H., Gan, Z., Jiang, W., Zhang, X., & Hua, Z. (2013) · Molecular BioSystems · doi:10.1039/c3mb70023b · Cited by 8
The role and intrinsic connection of cellular senescence and cell death in inflammatory bowel disease
Yang, L., & Yuan, L. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1502531 · Cited by 7
FADD regulates adipose inflammation, adipogenesis, and adipocyte survival
Tang, J., Ma, Y., Li, M., Liu, X., Wang, Y., Zhang, J., Shu, H. G., Liu, Z., Zhang, C., Fu, L., et al. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-02089-x · Cited by 7
“However, it remains unclear whether FADD de ﬁ ciency in adipocytes affects necroptosis, as reported in other cell types [18 – 20].”
Background
Mixed Lineage Kinase Domain-Like Pseudokinase (MLKL) Gene Expression in Human Atherosclerosis with and without Type 2 Diabetes Mellitus
Kamal, A. M., Sebak, S. A., & Sanad, E. F. (2021) · Iranian Biomedical Journal · doi:10.52547/ibj.25.4.265 · Cited by 9
“Many cytokines produced during the immune response are robust cell death inducers [13,40] .”
Background
MyD88-Dependent Signaling Is Required for HOIP Deficiency–Induced Autoinflammation
Wu, X. G., Tang, Y., Zhang, S., Zhao, X., & Lin, X. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2100173 · Cited by 8
Programmed Necrosis/Necroptosis: An Inflammatory Form of Cell Death
Chan, F. K.-M. (2013) · Springer eBooks · doi:10.1007/978-1-4614-9302-0_10 · Cited by 7
Modeling microbe-host interaction in the pathogenesis of Crohn’s disease
Ahmed, M., Metwaly, A., & Haller, D. (2021) · International Journal of Medical Microbiology · doi:10.1016/j.ijmm.2021.151489 · Cited by 6
Early Postnatal Comprehensive Biomarkers Cannot Identify Extremely Preterm Infants at Risk of Developing Necrotizing Enterocolitis
Hoffsten, A., Márkász, L., Lilja, H. E., Olsson, K. W., & Sindelar, R. (2021) · Frontiers in Pediatrics · doi:10.3389/fped.2021.755437 · Cited by 7
“Although no link has previously been made between FADD and NEC, FADD has been found to prevent intestinal inflammation (56), and knock-out of FADD has been shown to induce colitis (57).”
Background
A Risk Model Developed Based on Necroptosis Predicts Overall Survival for Hepatocellular Carcinoma and Identification of Possible Therapeutic Drugs
Li, Z., Fang, J., Chen, S., Liu, H., Zhou, J., Huang, J., Liu, S., & Peng, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.870264 · Cited by 7
“RIPK3-mediated epithelial necroptosis can lead to intestinal inflammation (8), and the lack of RIPK3 was shown to prevent skin inflammation in mice (9).”
Background
Harnessing Immunogenic Cell Death to Boost the Impact of Radiation Therapy
Mannion, J., & Meier, P. (2025) · The Cancer Journal · doi:10.1097/ppo.0000000000000780 · Cited by 6
TNFAIP3 ‐interacting protein 1 ( ABIN ‐1) negatively regulates caspase‐8/ FADD ‐dependent pyroptosis
Li, X., Wang, D., Su, Z., & Mao, X. (2025) · FEBS Journal · doi:10.1111/febs.17404 · Cited by 6
“FADD, similar to caspase-8, is normally regarded as an inhibitor of necroptosis [34,35].”
MTGR1 is required to maintain small intestinal stem cell populations
Short, S. P., Brown, R. E., Chen, Z., Pilat, J. M., McElligott, B. A., Meenderink, L. M., Bickart, A. C., Blunt, K. M., Jacobse, J., Wang, J., et al. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-024-01346-x · Cited by 6
Comparative proteomics analysis reveals roles for FADD in the regulation of energy metabolism and proteolysis pathway in mouse embryonic fibroblast
Zhuang, H., Gan, Z., Jiang, W., Zhang, X., & Hua, Z. (2013) · PROTEOMICS · doi:10.1002/pmic.201300017 · Cited by 6
Emphasising the European Union's Commitment to Cancer Research: A Helicopter View of the Seventh Framework Programme for Research and Technological Development
van de Loo, J., Trzaska, D., Berkouk, K., Vidal, M., & Draghia, R. (2012) · The Oncologist · doi:10.1634/theoncologist.2012-0327 · Cited by 6
What Is the Pathobiology of Inflammation to Cell Death? Apoptosis, Necrosis, Necroptosis, Autophagic Cell Death, Pyroptosis, and NETosis
Kang, R., & Tang, D. (2016) · Springer eBooks · doi:10.1007/978-3-319-30079-5_5 · Cited by 6
Necroptosis, ADAM proteases and intestinal (dys)function
Heib, M., Rose‐John, S., & Adam, D. (2020) · International review of cytology · doi:10.1016/bs.ircmb.2020.02.001 · Cited by 7
Bile Acids Induced Cell Necropotosis
Long, L. M. C. (2014) · Journal of Cytology & Histology · doi:10.4172/2157-7099.s4-004 · Cited by 6
“And when the Caspase-8 or FADD is expressed, RIPK3 induced programmed necrosis is obvious inhibition [37,38].”
Background
Molecular Pathways Disturbances during COVID-19 Lead to Cardiomyocyte NecroptosisPreprint
Sotoudeheian, M., Soleimani, M., Farahmandian, N., & Mirahmadi, S. (2023) · Preprints.org · doi:10.20944/preprints202304.0882.v1 · Cited by 5
Augmenting engraftment of beta cell replacement therapies for T1DM
Aggarwal, S., Pepper, A. R., & Jahdhami, N. A. (2021) · Journal of Immunology and Regenerative Medicine · doi:10.1016/j.regen.2021.100058 · Cited by 5
The ubiquitin ligase ITCH coordinates small intestinal epithelial homeostasis by modulating cell proliferation, differentiation, and migration
Mentrup, H. L., Hartman, A., Thames, E. L., Basheer, W. A., & Matesic, L. E. (2017) · Differentiation · doi:10.1016/j.diff.2017.12.003 · Cited by 5
“Further, defects in Paneth cell function have been described in IBD patients (Elphick and Mahida, 2005; Wehkamp et al., 2008) as well as in a number of mouse lines that develop spontaneous intestinal inflammation including Casp8IEC-KO (Gunther et al., 2011), FADDIEC-KO (Welz et al., 2011), NEMOIEC-KO (Nenci et al., 20…”
Background
Add necroptosis to your asthma action plan
Garnish, S. E., Crutchfield, E. C. T., Murphy, J. M., & Hildebrand, J. M. (2021) · Immunology and Cell Biology · doi:10.1111/imcb.12489 · Cited by 5
FADD phosphorylation contributes to development of renal fibrosis by accelerating epithelial-mesenchymal transition
Lin, Y., Cai, F., Wang, X., Yang, Y., Ren, Y., Yao, C., Yin, X., Zhuang, H., & Hua, Z. (2022) · Cell Cycle · doi:10.1080/15384101.2022.2136463 · Cited by 5
“Functionally, apart from its critical role in apoptosis, FADD also participates in many nonapoptotic activities, such as inflammation [4,5], autophagy [6,7], lymphocyte development and proliferation [8], cell cycle progression [9,10], embryonic development [11], tumorigenesis [12,13], glucose metabolism [14,15], and i…”
Background
Immunologic Repercussions of Cell Death
Beere, H. M., & Green, D. R. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-31696-5.00028-0 · Cited by 6
Abstracts from the BJA Research Forum
Cui, J., Zhao, H., Ma, D., Ciechanowicz, S., Zhao, H., Ma, D., Lee, M., Kciuk, O., Koelewyn, A., Beale, N., et al. (2016) · British Journal of Anaesthesia · doi:10.1093/bja/aev406 · Cited by 5
Discovery of quinazoline derivatives as RIPK3 inhibitors that switch cell death from necroptosis to apoptosis for psoriasis treatment
Hong, Y., Wu, Z., Jiang, J., Sun, Y., Ma, J.-H., Ai, J.-X., Wang, Y., Ma, D., Zhang, J., Yang, C. R., et al. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117716 · Cited by 5
Farnesoid X receptor inhibits proinflammatory cytokine-induced epithelial necroptosis in vitro: implications for preservation of intestinal barrier function
Curley, C. E., Lajczak, N., Adorini, L., Chonghaile, T. N., & Keely, S. J. (2025) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00086.2025 · Cited by 4
The role of apoptosis and its potential as a therapeutic target in inflammatory bowel disease associated with colorectal cancer
Zhang, C. (2025) · American Journal of Translational Research · doi:10.62347/ncff5626 · Cited by 7
Regulatory Role of Protein Ubiquitination in the Pathogenesis and Progression of Ulcerative Colitis
Zhu, Y., Liu, C., & Li, Y. (2025) · Journal of Digestive Diseases · doi:10.1111/1751-2980.70017 · Cited by 4
“Inhibition of CYLD activity effectively prevents colitis development in Fadd - deficient mice, as CYLD deubiquitylates RIPK1, promoting its interaction with RIPK3 to form a necroptotic complex, which triggers necroptosis [16].”

Authors: Welz, P.-S., Wullaert, A., Vlantis, K., Kondylis, V., Fernández-Majada, V., Ermolaeva, M., Kirsch, P., Sterner-Kock, A., van Loo, G., & Pasparakis, M.
Affiliations: University of Cologne (DE)
Universität Ulm (DE)
Corresponding author: Pasparakis, Manolis
ORCID: Welz, Patrick-Simon
Wullaert, Andy
Vlantis, Katerina
Kondylis, Vangelis
Ermolaeva, Maria
Pasparakis, Manolis
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2011-07-31
Volume: 477
Issue: 7364
Pages: 330-334
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature10273
OpenAlex: W1988848002
Cited by: 594
References: 36
Citations by year: 2026: 7 · 2025: 28 · 2024: 34 · 2023: 28 · 2022: 37 · 2021: 45 · 2020: 37 · 2019: 31 · 2018: 28 · 2017: 42 · 2016: 57 · 2015: 44 · 2014: 81 · 2013: 51 · 2012: 33
FWCI: 22.96
Type: journal article
Language: en
Open access: green
zenodo.org
Licence: other-oa
www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Ghent University Academic Bibliography (Ghent University) (submittedVersion)
Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords: FADD, RIPK3, necroptosis, epithelial cell necrosis, intestinal inflammation, Paneth cells, caspase-8, TNF-α, CYLD, NEMO, Toll-like receptor signaling, microbiota, Crohn's disease, intestinal epithelial cells, immune homeostasis, colitis, MyD88, commensal bacteria
MeSH terms: Deubiquitinating Enzyme CYLD, Animals, Chronic Disease, Colitis, Colon, Cysteine Endopeptidases, Enteritis, Epithelial Cells, Necrosis, Inflammatory Bowel Diseases, Signal Transduction, Apoptosis, Paneth Cells, Intracellular Signaling Peptides and Proteins, Tumor Necrosis Factors, Mice, Fas-Associated Death Domain Protein, Receptor-Interacting Protein Serine-Threonine Kinases, Myeloid Differentiation Factor 88, Metagenome

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FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation

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