Targeting RIPK3 oligomerization blocks necroptosis without inducing apoptosis.
FEBS Lett
; 594(14): 2294-2302, 2020 07.
Article
em En
| MEDLINE
| ID: mdl-32412649
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
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Apoptose
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Proteína Serina-Treonina Quinases de Interação com Receptores
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Multimerização Proteica
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Necroptose
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article