Targeting RIPK3 oligomerization blocks necroptosis without inducing apoptosis

  • FEBS Lett. 2020 Jul;594(14):2294-2302. doi: 10.1002/1873-3468.13812.
Wenjuan Li  1  2 ,  Hengxiao Ni  1  2 ,  Shaofeng Wu  1  2  3 ,  Shang Han  1  2  3 ,  Chang'an Chen  1  2 ,  Li Li  1  2  3 ,  Yunzhan Li  1  2  3 ,  Fu Gui  1  2  3 ,  Jiahuai Han  1  2 ,  Xianming Deng  1  2  3
Affiliations
  • 1. School of Life Sciences, Xiamen University, Xiamen, China.
  • 2. Cancer Research Center of Xiamen University, Xiamen, China.
  • 3. State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, China.
PMID: 32412649 DOI: 10.1002/1873-3468.13812
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.

Keywords
RIPK3; apoptosis; necroptosis; oligomerization; phosphorylation.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13805
    PP2
    99.14%, Src Inhibitor
    target: Src
    Research Areas: Cancer