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A Novel Role of Vimentin Filaments: Binding and Stabilization of Collagen mRNAs

机译:波形蛋白细丝的新型作用:胶原mRNA的结合和稳定。

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The stem-loop in the 5′ untranslated region (UTR) of collagen α1(I) and α2(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 α1(I) and α2(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 α1(I) and α2(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 α1(I) and α2(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.
机译:胶原α1(I)和α2(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素。胶原mRNA的稳定化是纤维化中胶原高表达的主要机制。 LARP6以高亲和力结合α1(I)和α2(I)mRNA的5'SL。在这里,我们报告波形蛋白细丝以5'SL和LARP6依赖的方式与胶原mRNA关联并稳定胶原mRNA。 LARP6通过其La结构域与波形蛋白丝相互作用,并与体内丝共定位。 LARP6的小干扰RNA(siRNA)的敲除或5'SL的突变消除了胶原mRNA与波形蛋白丝的相互作用。波形蛋白敲除成纤维细胞产生的I型胶原蛋白量减少,原因是胶原蛋白α1(I)和α2(I)mRNA的稳定性降低。使用药物或通过显性阴性结蛋白的表达破坏波形蛋白细丝会降低I型胶原蛋白的表达,这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α1(I)和α2(I)mRNA与体内波形蛋白细丝相关。因此,波形蛋白细丝可通过稳定胶原mRNA来在组织纤维化发展中发挥作用。该发现将作为在新型抗纤维化疗法发展中靶向波形蛋白的理由。

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