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

Autor: Seung Baek Lee, Khaled Aziz, Qifeng Luo, Zhenkun Lou, Fabienne C. Fiesel, Jin Ook Chung, Seo Yun Tong, Ping Yin, Yingfang Fan, Seon-Young Park, Asef Aziz, Jung Jin Kim, Li Sha Guo, Sung Il Choi, Wolfdieter Springer, Sung Sun Kim, Jin San Zhang, Sang Ah Han, Somaira Nowsheen
Rok vydání: 2019
Předmět:
Zdroj: Nature cell biology
ISSN: 1476-4679
1465-7392
DOI: 10.1038/s41556-019-0356-8
Popis: 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.
Databáze: OpenAIRE
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