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Updated: Apr 9, 2026
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A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
Published on: November 2, 2018
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RIPK1 ubiquitination regulates its kinase-independent function in development and inflammation
Ming Li1, Jianling Liu1, Mingyan Xing1
1Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Summary
Loss of RIPK1 ubiquitination at K376 causes embryonic lethality via cell death, but adult mice develop inflammation. This inflammation is RIPK1 kinase-independent and NLRP3 inflammasome-driven, mediated by RIPK3.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation.
- Ubiquitination of RIPK1 at lysine 376 (K376) inhibits apoptosis and necroptosis.
- The role of RIPK1 K376 ubiquitination in inflammation is not fully understood.
Purpose of the Study:
- To investigate the role of RIPK1 K376 ubiquitination in embryonic lethality and adult inflammation.
- To elucidate the mechanisms underlying RIPK1-mediated inflammation.
Main Methods:
- Generation of Ripk1K376R,D138N/K376R,D138N mice.
- Codeletion of Caspase-1/11, Trif, Ripk3, and Mlkl in Ripk1K376R mice.
- Analysis of embryonic lethality, systemic inflammation, and inflammasome activation.
Main Results:
- Ripk1K376R,D138N/K376R,D138N mice rescued embryonic lethality but developed systemic inflammation.
- Inflammation was alleviated by codeletion of Caspase-1/11, indicating inflammasome involvement.
- The K376R mutation induced RIPK1 kinase-independent inflammation via RIPK3 and NLRP3 inflammasome activation, independent of necroptosis.
Conclusions:
- Loss of RIPK1 ubiquitination at K376 causes embryonic lethality through kinase-dependent cell death.
- RIPK1K376R promotes kinase-independent inflammation via RIPK3-mediated NLRP3 inflammasome activation and IL-1β secretion.
- A RIPK3-dependent, necroptosis-independent inflammatory axis is identified, highlighting RIPK1's scaffold function in inflammation.
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