中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
A RIPK3-independent role of MLKL in suppressing parthanatos promotes immune evasion in hepatocellular carcinoma

文献类型:期刊论文

作者Jiang, Xifei1,2; Deng, Wenjia3,4; Tao, Siyao3,4; Tang, Zheng1,2; Chen, Yuehong3; Tian, Mengxin1,5; Wang, Ting3,4; Tao, Chenyang1,2; Li, Yize3,4; Fang, Yuan1,2
刊名CELL DISCOVERY
出版日期2023-01-17
卷号9期号:1页码:15
DOI10.1038/s41421-022-00504-0
通讯作者Liu, Weiren(liu.weiren@zs-hospital.sh.cn) ; Xu, Jun(kl_ds@126.com) ; Fan, Jia(fan.jia@zs-hospital.sh.cn) ; Shi, Yinghong(shi.yinghong@zs-hospital.sh.cn)
英文摘要Mixed lineage kinase domain-like (MLKL) is widely accepted as an executioner of necroptosis, in which MLKL mediates necroptotic signaling and triggers cell death in a receptor-interacting protein kinase 3 (RIPK3)-dependent manner. Recently, it is increasingly noted that RIPK3 is intrinsically silenced in hepatocytes, raising a question about the role of MLKL in hepatocellular carcinoma (HCC). This study reports a previously unrecognized role of MLKL in regulating parthanatos, a programmed cell death distinct from necroptosis. In HCC cells with intrinsic RIPK3 deficiency, knockout of MLKL impedes the orthotopic tumor growth, activates the anti-tumor immune response and enhances the therapeutic effect of immune checkpoint blockade in syngeneic HCC tumor models. Mechanistically, MLKL is required for maintaining the endoplasmic reticulum (ER)-mitochondrial Mg2+ dynamics in HCC cells. MLKL deficiency restricts ER Mg2+ release and mitochondrial Mg2+ uptake, leading to ER dysfunction and mitochondrial oxidative stress, which together confer increased susceptibility to metabolic stress-induced parthanatos. Importantly, pharmacological inhibition of poly(ADP-ribose) polymerase to block parthanatos restores the tumor growth and immune evasion in MLKL-knockout HCC tumors. Together, our data demonstrate a new RIPK3-independent role of MLKL in regulating parthanatos and highlight the role of MLKL in facilitating immune evasion in HCC.
WOS关键词NECROPTOSIS ; PROTEIN ; RIP3 ; MG2+ ; NECROSIS ; DOMAIN
资助项目National Natural Science Foundation of China[81903640] ; National Natural Science Foundation of China[81773067] ; National Natural Science Foundation of China[82073217] ; National Natural Science Foundation of China[82073218] ; National Natural Science Foundation of China[82003084] ; National Key Research and Development Program of China[2018YFC1312100] ; Shanghai Municipal Science and Technology Major Project[2018SHZDZX05] ; Shanghai Municipal Key Clinical Specialty, CAMS Innovation Fund for Medical Sciences[2019-I2M-5-058]
WOS研究方向Cell Biology
语种英语
出版者SPRINGERNATURE
WOS记录号WOS:000913321200001
源URL[http://119.78.100.183/handle/2S10ELR8/303564]  
专题新药研究国家重点实验室
通讯作者Liu, Weiren; Xu, Jun; Fan, Jia; Shi, Yinghong
作者单位1.Fudan Univ, Chinese Acad Med Sci, Zhongshan Hosp, Liver Canc Inst, Shanghai, Peoples R China
2.Canc Invas Minist Educ, Key Lab Carcinogenesis, Shanghai, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
4.Univ Chinese Acad Sci, Beijing, Peoples R China
5.Fudan Univ, Zhongshan Hosp, Dept Gen Surg, Shanghai, Peoples R China
6.Fudan Univ, Inst Biomed Sci, Shanghai, Peoples R China
7.Shanghai Key Lab Organ Transplantat, Shanghai, Peoples R China
8.Fudan Univ, Collaborat Innovat Ctr Genet & Dev, Sch Life Sci, State Key Lab Genet Engn, Shanghai, Peoples R China
推荐引用方式
GB/T 7714
Jiang, Xifei,Deng, Wenjia,Tao, Siyao,et al. A RIPK3-independent role of MLKL in suppressing parthanatos promotes immune evasion in hepatocellular carcinoma[J]. CELL DISCOVERY,2023,9(1):15.
APA Jiang, Xifei.,Deng, Wenjia.,Tao, Siyao.,Tang, Zheng.,Chen, Yuehong.,...&Shi, Yinghong.(2023).A RIPK3-independent role of MLKL in suppressing parthanatos promotes immune evasion in hepatocellular carcinoma.CELL DISCOVERY,9(1),15.
MLA Jiang, Xifei,et al."A RIPK3-independent role of MLKL in suppressing parthanatos promotes immune evasion in hepatocellular carcinoma".CELL DISCOVERY 9.1(2023):15.

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来源:上海药物研究所

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