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Necroptosis is a form of regulated programmed cell death that is mediated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting serine/threonine protein kinase-3 (RIPK3), and mixed lineage kinase domain-like protein (MLKL); however, it is not known whether zinc finger protein 91 (ZFP91) is involved in this process. Here, we investigated ZFP91 as a potential mediator of necroptosis. Our mechanistic study demonstrates that ZFP91 promotes RIPK1-RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. ZFP91 stabilized RIPK1 to promote cell death by inducing RIPK1 de-ubiquitination. ZFP91 also significantly increased production of mitochondrial reactive oxygen species (ROS). Accumulation of ROS promoted RIPK3-independent necroptosis triggered by tumor necrosis factor (TNF). in vivo, ZFP91 knockdown alleviated TNFα-induced systemic inflammatory response syndrome (SIRS). These results provide direct evidence that ZFP91 plays an important role in the initiation of RIPK1/RIPK3-dependent necroptosis in vitro and in vivo. We discussed the potential of ZFP91 as a novel therapeutic target for necroptosis-associated diseases. Copyright © 2021 Elsevier B.V. All rights reserved.

Citation

Yi Zhong, Zhi Hong Zhang, Jing Ying Wang, Yue Xing, Myong Hak Ri, Hong Lan Jin, Hong Xiang Zuo, Ming Yue Li, Juan Ma, Xuejun Jin. Zinc finger protein 91 mediates necroptosis by initiating RIPK1-RIPK3-MLKL signal transduction in response to TNF receptor 1 ligation. Toxicology letters. 2022 Mar 01;356:75-88

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PMID: 34942311

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