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

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 Fiesel, Wolfdieter Springer, Jin San Zhang, Zhenkun Lou

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)940-951
Number of pages12
JournalNature Cell Biology
Volume21
Issue number8
DOIs
StatePublished - Aug 1 2019

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Carcinogenesis
Inflammation
Receptor-Interacting Protein Serine-Threonine Kinases
AMP-Activated Protein Kinases
Ubiquitin-Protein Ligases
Parkinson Disease
Phosphorylation
Neoplasms

ASJC Scopus subject areas

  • Cell Biology

Cite this

The AMPK–Parkin axis negatively regulates necroptosis and tumorigenesis by inhibiting the necrosome. / 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; Springer, Wolfdieter; Zhang, Jin San; Lou, Zhenkun.

In: Nature Cell Biology, Vol. 21, No. 8, 01.08.2019, p. 940-951.

Research output: Contribution to journalArticle

Lee, SB, Kim, JJ, Han, SA, Fan, Y, Guo, LS, Aziz, K, Nowsheen, S, Kim, SS, Park, SY, Luo, Q, Chung, JO, Choi, SI, Aziz, A, Yin, P, Tong, SY, Fiesel, F, Springer, W, Zhang, JS & Lou, Z 2019, 'The AMPK–Parkin axis negatively regulates necroptosis and tumorigenesis by inhibiting the necrosome', Nature Cell Biology, vol. 21, no. 8, pp. 940-951. https://doi.org/10.1038/s41556-019-0356-8
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 ; Springer, Wolfdieter ; Zhang, Jin San ; Lou, Zhenkun. / The AMPK–Parkin axis negatively regulates necroptosis and tumorigenesis by inhibiting the necrosome. In: Nature Cell Biology. 2019 ; Vol. 21, No. 8. pp. 940-951.
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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.",
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