Journal
FEBS LETTERS
Volume 594, Issue 14, Pages 2294-2302Publisher
WILEY
DOI: 10.1002/1873-3468.13812
Keywords
apoptosis; necroptosis; oligomerization; phosphorylation; RIPK3
Funding
- National Key RD Program [2017YFA0504504, 2016YFA0502001]
- National Natural Science Foundation of China [81661138005, 91853203, 81630042, 31500737, 81603131]
- China Postdoctoral Science Foundation [2016M600505, 2017T100471]
- Fundamental Research Funds for the Central Universities of China [20720190101]
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Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) is a central protein in necroptosis with great potential as a target for treating necroptosis-associated diseases, such as Crohn's disease. However, blockade of RIPK3 kinase activity leads to unexpected RIPK3-initiated apoptosis. Herein, we found that PP2, a known SRC inhibitor, inhibits TNF-alpha-induced necroptosis without initiating apoptosis. Further investigation showed that PP2 acts as an inhibitor of not only SRC but also RIPK3. PP2 does not disturb the integrity of the RIPK1-RIPK3-mixed lineage kinase domain-like pseudokinase (MLKL) necroptosome or the autophosphorylation of RIPK3 at T231/S232 but disrupts RIPK3 oligomerization, thereby impairing the phosphorylation and oligomerization of MLKL. These results demonstrate the essential role of RIPK3 oligomerization in necroptosis and suggest a potential RIPK3 oligomerization-targeting strategy for therapeutic development.
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