DNA damage-inducible transcript 3 positively regulates RIPK1-mediated necroptosis

IF 13.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Death and Differentiation Pub Date : 2024-10-03 DOI:10.1038/s41418-024-01385-4
Rui Ni, Ting Cao, Xiaoyun Ji, Angel Peng, Zhuxu Zhang, Guo-Chang Fan, Peter Stathopulos, Subrata Chakrabarti, Zhaoliang Su, Tianqing Peng
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Abstract

DNA damage-inducible transcript 3 (DDIT3) is a well-known transcription factor that regulates the expression of apoptosis-related genes for promoting apoptosis during endoplasmic reticulum stress. Here, we report an unrecognized role of DDIT3 in facilitating necroptosis. DDIT3 directly binds and competitively prevents the p38 MAPK-MK2 interaction and thereby blocking MK2 activation while stimulating p38 MAPK activation. This blockage of MK2 activation initially prevents RIPK1 phosphorylation at Ser320 (inactivation), subsequently relieving its suppression of RIPK1 activation. Consequently, p38 MAPK facilitates RIPK1 phosphorylation at Ser166 (activation) through DDIT3 phosphorylation-related mechanisms, leading to necroptosis. Mechanistically, a 10-amino acid segment (Glu19-Val28) within DDIT3’s N-terminus is identified to account for its pro-necroptotic function. In vivo studies demonstrate that forced expression of DDIT3 induces necroptosis, whereas deletion of DDIT3 alleviates necroptosis in mouse hearts under stress. These findings shed light on a novel regulatory mechanism by which DDIT3 promotes RIPK1 activation and subsequent necroptosis.

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DNA 损伤诱导转录本 3 对 RIPK1 介导的坏死有正向调节作用
DNA 损伤诱导转录本 3(DDIT3)是一种众所周知的转录因子,它能调节凋亡相关基因的表达,从而在内质网应激时促进细胞凋亡。在这里,我们报告了 DDIT3 在促进坏死中的一个未被认识的作用。DDIT3 直接结合并竞争性阻止 p38 MAPK-MK2 相互作用,从而阻断 MK2 的激活,同时刺激 p38 MAPK 的激活。这种对 MK2 激活的阻断最初会阻止 RIPK1 在 Ser320 处的磷酸化(失活),随后解除对 RIPK1 激活的抑制。因此,p38 MAPK 通过 DDIT3 磷酸化相关机制促进 RIPK1 在 Ser166 处的磷酸化(激活),从而导致坏死。从机理上讲,DDIT3 N 端的一个 10 氨基酸片段(Glu19-Val28)被确定为其促坏死功能的原因。体内研究表明,强迫表达 DDIT3 会诱导小鼠心脏坏死,而缺失 DDIT3 则会缓解小鼠心脏在应激状态下的坏死。这些发现揭示了一种新的调控机制,即 DDIT3 通过这种机制促进 RIPK1 的活化和随后的坏死。
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来源期刊
Cell Death and Differentiation
Cell Death and Differentiation 生物-生化与分子生物学
CiteScore
24.70
自引率
1.60%
发文量
181
审稿时长
3 months
期刊介绍: Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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