Department of Plastic and Reconstructive Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Department of Plastic and Reconstructive Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Am J Pathol. 2019 Jul;189(7):1351-1362. doi: 10.1016/j.ajpath.2019.03.005. Epub 2019 Apr 10.
Wound healing is a process of cutaneous barrier reconstruction that occurs after skin injury and involves diverse cytokines and cell types. Similar to several deubiquitinating enzymes, ubiquitin-specific protease 15 (USP15) can remove ubiquitin chains from specific proteins to rescue them from degradation. However, the regulatory role of USP15 in wound healing remains unclear. We investigated the dynamic function of USP15 in wound healing. First, in USP15 knockout mice, we observed a significant delay in wound closure. In addition, inhibition of cell proliferation and migration was observed in USP15-silenced human dermal fibroblasts. Through RNA sequencing, it was revealed that the transforming growth factor-β (TGF-β) pathway was suppressed after USP15 knockdown. Furthermore, coimmunoprecipitation demonstrated that USP15 could interact with TGF-β receptor I and promote its deubiquitination, thereby maintaining TGF-β signaling pathway activity by enhancing TGF-β receptor I stability. These observations shed light on the function and mechanisms of USP15-mediated modulation of the TGF-β signaling pathway during wound healing, thus providing a novel potential target for the treatment of refractory wounds.
伤口愈合是皮肤损伤后发生的皮肤屏障重建过程，涉及多种细胞因子和细胞类型。与几种去泛素化酶类似，泛素特异性蛋白酶 15（USP15）可以从特定蛋白质上去除泛素链，以防止它们降解。然而，USP15 在伤口愈合中的调节作用尚不清楚。我们研究了 USP15 在伤口愈合中的动态功能。首先，在 USP15 敲除小鼠中，我们观察到伤口闭合明显延迟。此外，USP15 沉默的人真皮成纤维细胞中观察到细胞增殖和迁移的抑制。通过 RNA 测序，发现 USP15 敲低后转化生长因子-β（TGF-β）途径受到抑制。此外，免疫共沉淀表明 USP15 可以与 TGF-β 受体 I 相互作用并促进其去泛素化，从而通过增强 TGF-β 受体 I 的稳定性来维持 TGF-β 信号通路的活性。这些观察结果揭示了 USP15 介导的 TGF-β 信号通路在伤口愈合中的功能和机制，为治疗难治性伤口提供了一个新的潜在靶点。
