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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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Citations
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“Mice with an epidermis-specific RIPK1 deficiency (RIPK1 E-KO ) develop progressive inflammatory lesions defined by epidermal hyperplasia, aberrant differentiation marker expression, myeloid cell infiltration, and a robust surge in pro-inflammatory cytokines [76].”
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BindingDB Entry 50048252: Non-kinase targets of protein kinase inhibitors.
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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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