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Targeting RIPK3 oligomerization blocks necroptosis without inducing apoptosis
Author(s) -
Li Wenjuan,
Ni Hengxiao,
Wu Shaofeng,
Han Shang,
Chen Chang'an,
Li Li,
Li Yunzhan,
Gui Fu,
Han Jiahuai,
Deng Xianming
Publication year - 2020
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13812
Subject(s) - necroptosis , ripk1 , autophosphorylation , microbiology and biotechnology , phosphorylation , kinase , programmed cell death , protein kinase a , chemistry , biology , apoptosis , biochemistry
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‐α‐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.