• Home
  • Search Results
  • The AMPK-Parkin axis negatively regulates necroptosis and tumorigenesis by inhibiting the necrosome.

The AMPK-Parkin axis negatively regulates necroptosis and tumorigenesis by inhibiting the necrosome.

Nature cell biology (2019-07-31)
Seung Baek Lee, Jung Jin Kim, Sang-Ah Han, Yingfang Fan, Li-Sha Guo, Khaled Aziz, Somaira Nowsheen, Sung Sun Kim, Seon-Young Park, Qifeng Luo, Jin Ook Chung, Sung Il Choi, Asef Aziz, Ping Yin, Seo-Yun Tong, Fabienne C Fiesel, Wolfdieter Springer, Jin-San Zhang, Zhenkun Lou
ABSTRACT

The receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 play important roles in necroptosis that are closely linked to the inflammatory response. Although the activation of necroptosis is well characterized, the mechanism that tunes down necroptosis is largely unknown. Here we find that Parkin (also known as PARK2), an E3 ubiquitin ligase implicated in Parkinson's disease and as a tumour suppressor, regulates necroptosis and inflammation by regulating necrosome formation. Parkin prevents the formation of the RIPK1-RIPK3 complex by promoting polyubiquitination of RIPK3. Parkin is phosphorylated and activated by the cellular energy sensor AMP-activated protein kinase (AMPK). Parkin deficiency potentiates the RIPK1-RIPK3 interaction, RIPK3 phosphorylation and necroptosis. Parkin deficiency enhances inflammation and inflammation-associated tumorigenesis. These findings demonstrate that the AMPK-Parkin axis negatively regulates necroptosis by inhibiting RIPK1-RIPK3 complex formation; this regulation may serve as an important mechanism to fine-tune necroptosis and inflammation.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Azoxymethane, 13.4 M, ≥98%
Sigma-Aldrich
Carbonyl cyanide 3-chlorophenylhydrazone, ≥97% (TLC), powder
Sigma-Aldrich
Z-VAD-FMK, solid
Supelco
Residual Solvents Mixture - Class IIA, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
MISSION® esiRNA, targeting human PINK1, PINK1-AS