The Batten disease protein CLN3 is important for stress granules dynamics and translational activity.
The Batten disease protein CLN3 is important for stress granules dynamics and translational activity.
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DOI：
10.1016/j.jbc.2023.104649
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发表时间：
2023-05
影响因子：
4.8
通讯作者：
Locker, Nicolas
中科院分区：
文献类型：
--
作者：
Relton, Emily L.;Roth, Nicolas J.;Yasa, Seda;Kaleem, Abuzar;Hermey, Guido;Minnis, Christopher J.;Mole, Sara E.;Shelkovnikova, Tatyana;Lefrancois, Stephane;McCormick, Peter J.;Locker, Nicolas
无膜细胞器如应激颗粒（SG）的组装正在成为帮助细胞快速响应和适应应激的核心。在应激感测之后，所产生的全局翻译关闭导致停滞的mRNA和蛋白质缩合成SG。通过重组细胞质内容物，SGs可以调节RNA翻译，生化反应和信号级联，以促进生存，直到压力得到解决。虽然SG分解的机制还没有被广泛理解，但SG的分解对于维持细胞活力和蛋白质稳态是重要的。导致持续性或异常SG的突变越来越多地与神经病理学相关，并且是几种神经退行性疾病的标志。CLN3的突变是青少年神经元蜡样质脂褐质沉积症的原因，这是一种影响儿童的罕见神经退行性疾病，也称为Batten病。CLN3编码涉及自噬、内体运输、代谢和对氧化应激的响应的跨膜溶酶体蛋白。使用缺乏CLN3的HeLa细胞模型，我们现在表明CLN3KO与代谢谱改变、全局翻译减少和应激信号改变有关。此外，CLN3功能的丧失导致SG动力学的扰动，导致组装和拆卸缺陷，以及关键SG成核因子G3BP 1的表达改变。随着人们对用于治疗神经退行性疾病的SG调节药物的兴趣越来越大，对CLN3 Batten病的分子基础的新见解可能会揭示这种使人衰弱的儿童疾病的疾病修饰治疗的途径。
The assembly of membrane-less organelles such as stress granules (SGs) is emerging as central in helping cells rapidly respond and adapt to stress. Following stress sensing, the resulting global translational shutoff leads to the condensation of stalled mRNAs and proteins into SGs. By reorganizing cytoplasmic contents, SGs can modulate RNA translation, biochemical reactions, and signaling cascades to promote survival until the stress is resolved. While mechanisms for SG disassembly are not widely understood, the resolution of SGs is important for maintaining cell viability and protein homeostasis. Mutations that lead to persistent or aberrant SGs are increasingly associated with neuropathology and a hallmark of several neurodegenerative diseases. Mutations in CLN3 are causative of juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease affecting children also known as Batten disease. CLN3 encodes a transmembrane lysosomal protein implicated in autophagy, endosomal trafficking, metabolism, and response to oxidative stress. Using a HeLa cell model lacking CLN3, we now show that CLN3KO is associated with an altered metabolic profile, reduced global translation, and altered stress signaling. Furthermore, loss of CLN3 function results in perturbations in SG dynamics, resulting in assembly and disassembly defects, and altered expression of the key SG nucleating factor G3BP1. With a growing interest in SG-modulating drugs for the treatment of neurodegenerative diseases, novel insights into the molecular basis of CLN3 Batten disease may reveal avenues for disease-modifying treatments for this debilitating childhood disease.
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DOI：
10.1074/jbc.ra120.015398
发表时间：
2020-12-18
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Klickstein JA;Mukkavalli S;Raman M
通讯作者：
Raman M
DOI：
10.1083/jcb.201709072
发表时间：
2018-01-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
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通讯作者：
Hartl FU
影响因子：
4.8
作者：
Chandrachud, Uma;Walker, Mathew W.;Cotman, Susan L.
通讯作者：
Cotman, Susan L.
G3BP1促进应力诱导的RNA颗粒相互作用，以保留多腺苷酸化的mRNA。
DOI：
10.1083/jcb.201408092
发表时间：
2015-04-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Aulas A;Caron G;Gkogkas CG;Mohamed NV;Destroismaisons L;Sonenberg N;Leclerc N;Parker JA;Vande Velde C
通讯作者：
Vande Velde C
影响因子：
13.8
作者：
Kedersha, Nancy;Ivanov, Pavel;Anderson, Paul
通讯作者：
Anderson, Paul