Optogenetic control of the integrated stress response reveals proportional encoding and the stress memory landscape.

IF 9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Taivan Batjargal, Francesca Zappa, Ryan J Grant, Robert A Piscopio, Alex Chialastri, Siddharth S Dey, Diego Acosta-Alvear, Maxwell Z Wilson
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引用次数: 0

Abstract

The integrated stress response (ISR) is a conserved signaling network that detects aberrations and computes cellular responses. Dissecting these computations has been difficult because physical and chemical inducers of stress activate multiple parallel pathways. To overcome this challenge, we engineered a photo-switchable control over the ISR sensor kinase PKR (opto-PKR), enabling virtual, on-target activation. Using light to control opto-PKR dynamics, we traced information flow through the transcriptome and for key downstream ISR effectors. Our analyses revealed a biphasic, proportional transcriptional response with two dynamic modes, transient and gradual, that correspond to adaptive and terminal outcomes. We then constructed an ordinary differential equation (ODE) model of the ISR, which demonstrated the dependence of future stress responses on past stress. Finally, we tested our model using high-throughput light-delivery to map the stress memory landscape. Our results demonstrate that cells encode information in stress levels, durations, and the timing between encounters. A record of this paper's transparent peer review process is included in the supplemental information.

Abstract Image

光遗传控制的综合应激反应揭示了比例编码和应激记忆景观。
综合应激反应(ISR)是一个保守的信号网络,可以检测畸变并计算细胞反应。解剖这些计算一直很困难,因为应力的物理和化学诱导剂激活了多个平行途径。为了克服这一挑战,我们设计了一种对ISR传感器激酶PKR (optopkr)的光开关控制,实现了虚拟的靶标激活。利用光来控制光pkr动力学,我们追踪了转录组和关键下游ISR效应子的信息流。我们的分析揭示了一种双相的、比例的转录反应,具有两种动态模式,短暂的和渐进的,对应于适应性和终末结果。然后,我们构建了ISR的常微分方程(ODE)模型,该模型证明了未来应力响应对过去应力的依赖性。最后,我们使用高通量光传输来测试我们的模型,以绘制压力记忆景观。我们的研究结果表明,细胞在压力水平、持续时间和遭遇之间的时间间隔中编码信息。本文的透明同行评议过程记录包含在补充信息中。
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 Systems
Cell Systems Medicine-Pathology and Forensic Medicine
CiteScore
16.50
自引率
1.10%
发文量
84
审稿时长
42 days
期刊介绍: In 2015, Cell Systems was founded as a platform within Cell Press to showcase innovative research in systems biology. Our primary goal is to investigate complex biological phenomena that cannot be simply explained by basic mathematical principles. While the physical sciences have long successfully tackled such challenges, we have discovered that our most impactful publications often employ quantitative, inference-based methodologies borrowed from the fields of physics, engineering, mathematics, and computer science. We are committed to providing a home for elegant research that addresses fundamental questions in systems biology.
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