A Novel Role of Vimentin Filaments: Binding and Stabilization of Collagen mRNAs
A Novel Role of Vimentin Filaments: Binding and Stabilization of Collagen mRNAs
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DOI：
10.1128/mcb.05263-11
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发表时间：
2011-09-01
影响因子：
5.3
通讯作者：
Stefanovic, Branko
中科院分区：
文献类型：
--
作者：
Challa, Azariyas A.;Stefanovic, Branko
胶原α 1（I）和α 2（I）mRNA（5 'SL）的5'非翻译区（UTR）中的茎环是调节其稳定性和翻译的关键元件。胶原mRNA的稳定化是纤维化中高胶原表达的主要机制。LARP 6以高亲和力结合α 1（I）和α 2（I）mRNA的5 'SL。在这里，我们报告，波形蛋白丝与胶原蛋白的mRNA在5 'SL-和LARP 6依赖的方式和稳定胶原蛋白的mRNA。LARP 6通过其La结构域与波形蛋白丝相互作用，并在体内与丝共定位。通过小干扰RNA（siRNA）或5 'SL的突变敲低LARP 6消除胶原mRNA与波形蛋白细丝的相互作用。波形蛋白敲除的成纤维细胞由于胶原α 1（I）和α 2（I）mRNA的稳定性降低而产生减少量的I型胶原。使用药物或通过显性负结蛋白表达破坏波形蛋白细丝会降低I型胶原蛋白表达，主要是由于胶原蛋白mRNA的稳定性降低。RNA荧光原位杂交（FISH）实验表明，胶原α 1（I）和α 2（I）mRNA与波形蛋白丝在体内。因此，波形蛋白丝可能通过稳定胶原mRNA在组织纤维化的发展中发挥作用。这一发现将作为一个理论基础，针对波形蛋白在新的抗纤维化治疗的发展。
The stem-loop in the 5' untranslated region (UTR) of collagen alpha 1(I) and alpha 2(I) mRNAs (5'SL) is the key element regulating their stability and translation. Stabilization of collagen mRNAs is the predominant mechanism for high collagen expression in fibrosis. LARP6 binds the 5'SL of alpha 1(I) and alpha 2(I) mRNAs with high affinity. Here, we report that vimentin filaments associate with collagen mRNAs in a 5'SL- and LARP6-dependent manner and stabilize collagen mRNAs. LARP6 interacts with vimentin filaments through its La domain and colocalizes with the filaments in vivo. Knockdown of LARP6 by small interfering RNA (siRNA) or mutation of the 5'SL abrogates the interaction of collagen mRNAs with vimentin filaments. Vimentin knockout fibroblasts produce reduced amounts of type I collagen due to decreased stability of collagen alpha 1(I) and alpha 2(I) mRNAs. Disruption of vimentin filaments using a drug or by expression of dominant-negative desmin reduces type I collagen expression, primarily due to decreased stability of collagen mRNAs. RNA fluorescence in situ hybridization (FISH) experiments show that collagen alpha 1(I) and alpha 2(I) mRNAs are associated with vimentin filaments in vivo. Thus, vimentin filaments may play a role in the development of tissue fibrosis by stabilizing collagen mRNAs. This finding will serve as a rationale for targeting vimentin in the development of novel antifibrotic therapies.