Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA.
Mol Cell Biol. 2011 Sep;31(18):3773-89. doi: 10.1128/MCB.05263-11. Epub 2011 Jul 11.
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.
胶原 α1(I) 和 α2(I) mRNA（5' 非翻译区（UTR）的茎环结构是调节其稳定性和翻译的关键元件。胶原 mRNA 的稳定是纤维化中高胶原表达的主要机制。LARP6 以高亲和力结合 α1(I) 和 α2(I) mRNA 的 5'SL。在这里，我们报告说中间丝蛋白 vimentin 以 5'SL 和 LARP6 依赖性的方式与胶原 mRNA 相关联，并稳定胶原 mRNA。LARP6 通过其 La 结构域与中间丝蛋白相互作用，并在体内与纤维丝共定位。通过小干扰 RNA（siRNA）敲低 LARP6 或突变 5'SL 会破坏胶原 mRNA 与中间丝蛋白的相互作用。LARP6 的 siRNA 敲低或 5'SL 的突变会导致 vimentin 缺失的成纤维细胞中 I 型胶原的产生减少，这主要是由于胶原 α1(I) 和 α2(I) mRNA 的稳定性降低。使用药物或表达显性负性的结蛋白破坏中间丝蛋白会降低 I 型胶原的表达，主要是由于胶原 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 在体内与 vimentin 纤维蛋白相关联。因此，中间丝蛋白可能通过稳定胶原 mRNA 在组织纤维化的发展中发挥作用。这一发现将为靶向中间丝蛋白在新型抗纤维化治疗中的开发提供依据。
