The cold-inducible RNA-binding protein migrates from the nucleus to cytoplasmic stress granules by a methylation-dependent mechanism and acts as a translational repressor
The cold-inducible RNA-binding protein migrates from the nucleus to cytoplasmic stress granules by a methylation-dependent mechanism and acts as a translational repressor
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DOI：
10.1016/j.yexcr.2007.09.017
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发表时间：
2007-12-10
影响因子：
3.7
通讯作者：
Gueydan, Cyril
中科院分区：
文献类型：
--
作者：
De Leeuw, Frederic;Zhang, Tong;Gueydan, Cyril
冷诱导RNA结合蛋白(CIRP)是由一个氨基末端的RNA识别基序(RRM)和一个含有多个RGG基序的羧基末端组成的核18 kDa蛋白质。CIRP最初的特征是在冷休克时过度表达，在紫外线照射和低氧等应激条件下也会诱导。在这里，我们研究了CIRP的表达以及在其他应激条件下的亚细胞定位。我们证明，氧化应激导致CIRP迁移到应激颗粒(SGS)，而不改变表达。应激颗粒是一种动态的细胞质焦点，在受环境胁迫的细胞中，停滞不前的翻译起始复合体聚集在这里。CIRP在SGS中的重新定位也发生在其他细胞质胁迫(渗透压或热休克)以及对内质网胁迫的反应中。CIRP向SGS的迁移独立于TIA-1，TIA-1已被报道为SG形成的一般介质，因此表明存在多种导致SG形成的途径。此外，缺失突变体表明，RGG和RRM结构域都可以独立地促进CIRP向SGS的迁移。然而，RGG结构域中精氨酸残基的甲基化是CIRP离开细胞核进一步招募到SGS所必需的。通过RNA拴系实验，我们还表明CIRP下调了mRNA的翻译，并且这一活性是由羧基末端的RG富集区承载的。总之，我们的发现进一步揭示了CIRP受环境胁迫调控的机制的多样性，并为CIRP细胞质功能提供了新的见解。(C)2007 Elsevier Inc.保留所有权利。
The cold-inducible RNA-binding protein (CIRP) is a nuclear 18-kDa protein consisting of an amino-terminal RNA Recognition Motif (RRM) and a carboxyl-terminal domain containing several RGG motifs. First characterized for its overexpression upon cold shock, CIRP is also induced by stresses such as UV irradiation and hypoxia. Here, we investigated the expression as well as the subcellular localization of CIRP in response to other stress conditions. We demonstrate that oxidative stress leads to the migration of CIRP to stress granules (SGs) without alteration of expression. Stress granules are dynamic cytoplasmic foci at which stalled translation initiation complexes accumulate in cells subjected to environmental stress. Relocalization of CIRP into SGs also occurs upon other cytoplasmic stresses (osmotic pressure or heat shock) as well as in response to stresses of the endoplasmic reticulum. CIRP migration into SGs is independent from TIA-1 which has been previously reported to be a general mediator of SG formation, thereby suggesting the existence of multiple pathways leading to SG formation. Moreover, deletion mutants revealed that both RGG and RRM domains can independently promote CIRP migration into SGs. However, the methylation of arginine residues in the RGG domain is necessary for CIRP to exit the nucleus to be further recruited into SGs. By RNA-tethering experiments, we also show that CIRP down-regulates mRNA translation and that this activity is carried by the carboxyl-terminal RG-enriched domain. Altogether, our findings further reveal the diversity of mechanisms by which CIRP is regulated by environmental stresses and provide new insights into CIRP cytoplasmic function. (c) 2007 Elsevier Inc. All rights reserved.