Regulation of translation elongation and integrated stress response in heat-shocked neurons.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-04-24 DOI:10.1016/j.celrep.2025.115639

Caitlin M Seluzicki, Milad Razavi-Mohseni, Fulya Türker, Priyal Patel, Boyang Hua, Michael A Beer, Loyal Goff, Seth S Margolis

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Abstract

Neurons deviate from a canonical heat shock response (HSR). Here, we revealed that neuronal adaptation to heat shock accompanies a brake on mRNA translation, slowed elongating ribosomes, phosphorylation of eukaryotic elongation factor-2 (p-eEF2), and suppressed the integrated stress response (ISR). Returning neurons to control temperature within 1 h of starting heat shock was necessary for survival and allowed for restored translation following dephosphorylation of eEF2. Subsequent to recovery, neurons briefly activated the ISR and were sensitive to the ISR inhibitor ISRIB, which enhanced protein synthesis and survival. Ribosome profiling and RNA sequencing (RNA-seq) identified newly synthesized and existing transcripts associated with ribosomes during heat shock. Preservation of these transcripts for translation during recovery was in part mediated by p-eEF2 and slowed ribosomes. Our work supports a neuronal heat shock model of a partially suspended state of translation poised for rapid reversal if recovery becomes an option and provides insight into regulation between the HSR and the ISR.

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热休克神经元翻译延伸和综合应激反应的调控。

神经元偏离典型热休克反应（HSR）。在这里，我们发现神经元对热休克的适应伴随着mRNA翻译的中断，延长核糖体的减慢，真核延伸因子-2 （p-eEF2）的磷酸化，并抑制综合应激反应（ISR）。在热休克开始后1小时内恢复神经元控制温度是存活所必需的，并允许在eEF2去磷酸化后恢复翻译。恢复后，神经元短暂激活ISR，并对ISR抑制剂ISRIB敏感，从而增强蛋白质合成和存活。核糖体分析和RNA测序（RNA-seq）鉴定了热休克期间新合成的和现有的与核糖体相关的转录物。在恢复过程中，这些转录本的保存部分是由p-eEF2和慢速核糖体介导的。我们的工作支持了一个部分暂停翻译状态的神经元热休克模型，如果恢复成为一种选择，该模型准备快速逆转，并为高铁和低铁之间的调控提供了见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.