Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, USA.
Wiley Interdiscip Rev RNA. 2013 Sep-Oct;4(5):535-45. doi: 10.1002/wrna.1177. Epub 2013 May 28.
Type I collagen is the most abundant protein in human body. The protein turns over slowly and its replacement synthesis is low. However, in wound healing or in pathological fibrosis the cells can increase production of type I collagen several hundred fold. This increase is predominantly due to posttranscriptional regulation, including increased half-life of collagen messenger RNAs (mRNAs) and their increased translatability. Type I collagen is composed of two α1 and one α2 polypeptides that fold into a triple helix. This stoichiometry is strictly regulated to prevent detrimental synthesis of α1 homotrimers. Collagen polypeptides are co-translationally modified and the rate of modifications is in dynamic equilibrium with the rate of folding, suggesting coordinated translation of collagen α1(I) and α2(I) polypeptides. Collagen α1(I) mRNA has in the 3' untranslated region (UTR) a C-rich sequence that binds protein αCP, this binding stabilizes the mRNA in collagen producing cells. In the 5' UTR both collagen mRNAs have a conserved stem-loop (5' SL) structure. The 5' SL is critical for high collagen expression, knock in mice with disruption of the 5' SL are resistant to liver fibrosis. the 5' SL binds protein LARP6 with strict sequence specificity and high affinity. LARP6 recruits RNA helicase A to facilitate translation initiation and associates collagen mRNAs with vimentin and nonmuscle myosin filaments. Binding to vimentin stabilizes collagen mRNAs, while nonmuscle myosin regulates coordinated translation of α1(I) and α2(I) mRNAs. When nonmuscle myosin filaments are disrupted the cells secrete only α1 homotrimers. Thus, the mechanism governing high collagen expression involves two RNA binding proteins and development of cytoskeletal filaments.
Ⅰ型胶原是人体内最丰富的蛋白质。该蛋白质更新缓慢，其替换合成率低。然而，在伤口愈合或病理性纤维化中，细胞可以使Ⅰ型胶原的产生增加几百倍。这种增加主要归因于转录后调控，包括胶原信使 RNA（mRNA）半衰期的延长及其翻译能力的增加。Ⅰ型胶原由两条α1 和一条α2 多肽组成，折叠成三螺旋。这种化学计量比受到严格调控，以防止有害的α1 同源三聚体的合成。胶原多肽在共翻译过程中发生修饰，修饰的速度与折叠的速度处于动态平衡，这表明α1（I）和α2（I）胶原多肽的翻译是协调进行的。胶原α1（I）mRNA 在 3'非翻译区（UTR）中有一个富含 C 的序列，该序列与蛋白αCP 结合，这种结合使胶原产生细胞中的 mRNA 稳定。在 5'UTR 中，两种胶原 mRNA 都有一个保守的茎环（5' SL）结构。5' SL 对于高胶原表达至关重要，敲除 5' SL 的小鼠对肝纤维化具有抗性。5' SL 与 LARP6 具有严格的序列特异性和高亲和力结合。LARP6 招募 RNA 解旋酶 A 以促进翻译起始，并使胶原 mRNA 与波形蛋白和非肌球蛋白丝结合。与波形蛋白的结合稳定了胶原 mRNA，而非肌球蛋白调节α1（I）和α2（I）mRNA 的协调翻译。当非肌球蛋白丝被破坏时，细胞只分泌α1 同源三聚体。因此，调控高胶原表达的机制涉及两个 RNA 结合蛋白和细胞骨架丝的发育。
