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Updated: Apr 25, 2026
Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis
Marius Dannappel1, Katerina Vlantis1, Snehlata Kumari1
11] Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany [2].
Abstract:
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.
Insights
Receptor-interacting protein kinase 1 (RIPK1) prevents programmed cell death and inflammation in epithelial tissues. RIPK1
Area of Science:
- Cellular biology
- Immunology
- Developmental biology
Background:
- Necroptosis is a key programmed cell death pathway involved in development, homeostasis, immunity, and inflammation.
- RIPK1 is known to be involved in inflammatory and cell death signaling, with its kinase activity driving RIPK3-mediated necroptosis.
Purpose of the Study:
- To investigate the role of RIPK1's kinase-independent scaffolding functions in regulating homeostasis and preventing inflammation in barrier tissues.
- To elucidate RIPK1's mechanisms in inhibiting epithelial cell apoptosis and necroptosis.
Main Methods:
- Generated intestinal epithelial cell (IEC)-specific RIPK1 knockout mice.
- Utilized FADD ablation and RIPK1 kinase-inactive knock-in models.
- Performed epidermis-specific RIPK1 knockout experiments.
- Analyzed pathology in relation to microbiota and MyD88 signaling.
- Assessed the impact of TNFR1 deficiency.
Main Results:
- IEC-specific RIPK1 knockout led to apoptosis, villus atrophy, cell loss, and premature death, independent of microbiota and MyD88 signaling.
- Epithelial FADD ablation rescued premature death in RIPK1 knockout mice, but combined RIPK1 and FADD deficiency caused RIPK3-dependent necroptosis and inflammation.
- RIPK1 kinase inactivity only partially rescued FADD-deficient epithelial cell inflammation, indicating RIPK3-dependent necroptosis partly requires RIPK1 kinase activity.
- Epidermis-specific RIPK1 knockout caused keratinocyte apoptosis and necroptosis, leading to severe skin inflammation prevented by RIPK3 deficiency.
Conclusions:
- RIPK1's kinase-independent scaffolding functions are crucial for maintaining epithelial homeostasis and preventing inflammation in barrier tissues.
- RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo.
- Necroptosis is a more potent trigger of inflammation than apoptosis.
- RIPK1 acts as a master regulator of epithelial cell survival, homeostasis, and inflammation in the intestine and skin.
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