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

• Published in: Nature cell biology Vol. 21; no. 8; pp. 940 - 951
• Main Authors: Lee, Seung Baek, Kim, Jung Jin, Han, Sang-Ah, Fan, Yingfang, Guo, Li-Sha, Aziz, Khaled, Nowsheen, Somaira, Kim, Sung Sun, Park, Seon-Young, Luo, Qifeng, Chung, Jin Ook, Choi, Sung Il, Aziz, Asef, Yin, Ping, Tong, Seo-Yun, Fiesel, Fabienne C., Springer, Wolfdieter, Zhang, Jin-San, Lou, Zhenkun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2019; Nature Publishing Group
• Subjects: 13; 13/1; 13/51; 13/89; 13/95; 14/34; 14/35; 14/63; 38; 42; 59; 631/250/256; 631/337/474/2073; 631/80/82/2344; 64/60; 692/699/67; 82/29; 96/109; AMP; AMP-activated protein kinase; Animals; Apoptosis - physiology; Biomedical and Life Sciences; Cancer Research; Carcinogenesis; Carcinogenesis - genetics; Cell Biology; Cell death; Cell Transformation, Neoplastic - genetics; Complex formation; Cyclic adenylic acid; Development and progression; Developmental Biology; Health aspects; Inflammation; Inflammation - metabolism; Inflammatory response; Kinases; Life Sciences; Ligases; Medical research; Medicine, Experimental; Mice, Knockout; Necroptosis; Necrosis - physiopathology; Parkin protein; Parkinson's disease; Phosphorylation; Phosphorylation - physiology; Physiological aspects; Protein deficiency; Protein kinases; Proteins; Serine; Stem Cells; Threonine; Tumorigenesis; Tumors; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination - physiology; United States
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-019-0356-8

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. AMPK and Parkin keep the necrosome in check. Lee et al. show that AMPK activates Parkin and prevents RIPK1−RIPK3 complex formation by promoting RIPK3 ubiquitination, thereby negatively regulating necroptosis, inflammation and tumour initiation.