Neuronal Protein 3.1 Deficiency Leads to Reduced Cutaneous Scar Collagen Deposition and Tensile Strength due to Impaired Transforming Growth Factor-β1 to -β3 Translation

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• 作者：Tao Cheng^&lowast ; ; Michael Yue^&lowast ; ; Muhammad Nadeem Aslam^&dagger ; ; Xin Wang^&Dagger ; ; Gajendra Shekhawat^&Dagger ; ; James Varani^&dagger ; ; Lucia Schuger^&lowast ; ; ^{lschuger@bsd.uchicago.edu}
• 刊名：The American Journal of Pathology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：187
• 期：2
• 页码：292-303
• 全文大小：2013 K
• 卷排序：187

文摘

Neuronal protein 3.1 (P311), a conserved RNA-binding protein, represents the first documented protein known to stimulate transforming growth factor (TGF)-β1 to -β3 translation in vitro and in vivo. Because TGF-βs play critical roles in fibrogenesis, we initiated efforts to define the role of P311 in skin scar formation. Here, we show that P311 is up-regulated in skin wounds and in normal and hypertrophic scars. Genetic ablation of p311 resulted in a significant decrease in skin scar collagen deposition. Lentiviral transfer of P311 corrected the deficits, whereas down-regulation of P311 levels by lentiviral RNA interference reproduced the deficits seen in P311−/− mice. The decrease in collagen deposition resulted in scars with reduced stiffness but also reduced scar tensile strength. In vitro studies using murine and human dermal fibroblasts showed that P311 stimulated TGF-β1 to -β3 translation, a process that involved eukaryotic translation initiation factor 3 subunit b as a P311 binding partner. This resulted in increased TGF-β levels/activity and increased collagen production. In addition, P311 induced dermal fibroblast activation and proliferation. Finally, exogenous TGF-β1 to -β3, each restituted the normal scar phenotype. These studies demonstrate that P311 is required for the production of normal cutaneous scars and place P311 immediately up-stream of TGF-βs in the process of fibrogenesis. Conditions that decrease P311 levels could result in less tensile scars, which could potentially lead to higher incidence of dehiscence after surgery.