Epigenetic regulation of translation repression in ferroptosis, and a role of Alternative splicing and tRNA methylation
Epigenetic regulation of translation repression in ferroptosis, and a role of Alternative splicing and tRNA methylation
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DOI：
10.1101/2021.11.10.468143
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发表时间：
2021-11
期刊：
影响因子：
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通讯作者：
Sherif Rashad;D. Saigusa;Yuan Zhang;Liyin Zhang;T. Tominaga;Kuniyasu Niizuma
中科院分区：
文献类型：
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作者：
Sherif Rashad;D. Saigusa;Yuan Zhang;Liyin Zhang;T. Tominaga;Kuniyasu Niizuma
铁凋亡是一种非凋亡性细胞死亡机制，其特征在于脂质过氧化物的产生。亚铁凋亡在许多疾病如癌症和神经退行性疾病中起重要作用。虽然已经绘制了铁凋亡途径中的许多效应子，但其表观遗传和表转录调控过程尚未完全理解。可通过系统xCT抑制（I类）或GPX4抑制（II类）诱导铁凋亡。以前的工作已经揭示了重要的差异，细胞反应的I类和II类铁凋亡诱导剂。重要的是，阻断mRNA转录或翻译似乎可以保护细胞免受I类铁凋亡诱导剂的影响，而不是II类。了解这些微妙的差异是重要的，在理解以及在开发基于各种疾病的铁下垂的治疗。在这项工作中，我们研究了阻断转录（通过放线菌素D）或翻译（通过环己酰亚胺）对Erastin（I类）或RSL3（II类）诱导的铁凋亡的影响。阻断转录或翻译可保护细胞免受Erastin的侵害，但对RSL3有害。环己酰亚胺单独或与Erastin共处理时导致GSH水平升高，并激活反向转硫途径。RNA测序分析揭示了选择性剪接（AS）在调节铁凋亡应激反应和mRNA翻译抑制中的重要和未探索的作用。我们的研究结果表明，翻译抑制对Erastin具有保护作用，但对RSL3不利。我们在过表达Alkbh 1的胶质瘤细胞中测试了这一理论。Alkbh1使tRNA去甲基化并抑制翻译，与胶质瘤患者的预后不良相关。我们的研究结果表明，Alkbh 1过表达保护神经胶质瘤细胞对Erastin，但对RSL3是有害的。
Ferroptosis is a non-apoptotic cell death mechanism characterized by the production of lipid peroxides. Ferroptosis plays important roles in many diseases such as cancer and neurodegenerative diseases. While many effectors in the ferroptosis pathway have been mapped, its epigenetic and epitranscriptional regulatory processes are not yet fully understood. Ferroptosis can be induced via system xCT inhibition (Class I) or GPX4 inhibition (Class II). Previous works have revealed important differences in cellular response to Class I and Class II ferroptosis inducers. Importantly, blocking mRNA transcription or translation appears to protect cells against Class I ferroptosis inducing agents but not Class II. Understanding these subtle differences is important in understanding ferroptosis as well as in developing therapeutics based on ferroptosis for various diseases. In this work, we examined the impact of blocking transcription (via Actinomycin D) or translation (via Cycloheximide) on Erastin (Class I) or RSL3 (Class II) induced ferroptosis. Blocking transcription or translation protected cells against Erastin but was detrimental against RSL3. Cycloheximide led to increased levels of GSH alone or when co-treated with Erastin and the activation of the reverse transsulfuration pathway. RNA sequencing analysis revealed an important and unexplored role of Alternative splicing (AS) in regulating ferroptosis stress response and mRNA translation repression. Our results indicated that translation repression is protective against Erastin but detrimental against RSL3. We tested this theory in Alkbh1 overexpressing glioma cells. Alkbh1 demethylates tRNA and represses translation and is associated with worse outcome in glioma patients. Our results showed that Alkbh1 overexpression protected glioma cells against Erastin but was detrimental against RSL3.