한빛사 논문
Seung Baek Lee1,15, Jung Jin Kim1,15, Sang-Ah Han2, Yingfang Fan3, Li-Sha Guo4, Khaled Aziz5, Somaira Nowsheen5, Sung Sun Kim6, Seon-Young Park7, Qifeng Luo8, Jin Ook Chung7, Sung Il Choi2, Asef Aziz9,10, Ping Yin1, Seo-Yun Tong11, Fabienne C. Fiesel 12,13, Wolfdieter Springer12,13, Jin-San Zhang1,4,14* and Zhenkun Lou1*
1 Division of Oncology Research, Mayo Clinic, Rochester, MN, USA. 2 Department of Surgery, School of Medicine, Kyung Hee University, Seoul, Republic of Korea. 3 Department of Hepatobiliary Surgery, Zhujiang Hospital of the Southern Medical University, Guangzhou, China. 4 School of Pharmaceutical Sciences, Wenzhou Medical University, Zhejiang, China. 5 Mayo Clinic Medical Scientist Training Program, Mayo Clinic Alix School of Medicine and Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA. 6 Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea. 7 Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea. 8 Department of General Surgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China. 9 Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA. 10 Saint Louis University School of Medicine, Saint Louis, MO, USA. 11 Segaon Women’s Hospital, Gangneung, Republic of Korea. 12 Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. 13 Neuroscience Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA. 14 The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China. 15 These authors contributed equally: Seung Baek Lee, Jung Jin Kim.
*Correspondence to Jin-San Zhang or 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.
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