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 |
DOI | 10.1038/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. |
入库方式: OAI收割
来源:上海药物研究所
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