Ubiquitin-Specific Protease 15 Maintains Transforming Growth Factor-β Pathway Activity by Deubiquitinating Transforming Growth Factor-β Receptor I during Wound Healing
Ubiquitin-Specific Protease 15 Maintains Transforming Growth Factor-β Pathway Activity by Deubiquitinating Transforming Growth Factor-β Receptor I during Wound Healing
复制标题
泛素特异性蛋白酶 15 在伤口愈合过程中通过去泛素化转化生长因子-β 受体 I 来维持转化生长因子-β 通路活性
DOI：
10.1016/j.ajpath.2019.03.005
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发表时间：
2019
影响因子：
6
通讯作者：
Qingfeng Li
中科院分区：
文献类型：
--
作者：
Yixuan Zhao;Zi Wang;Chiakang Ho;Guoyou Zhang;Qingfeng Li
创面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。与几种脱泛素化酶类似，泛素特异蛋白酶15(USP15)可以去除特定蛋白质中的泛素链，使其免于降解。然而，USP15在伤口愈合中的调节作用仍不清楚。我们研究了USP15在伤口愈合中的动态作用。首先，在USP15基因敲除的小鼠中，我们观察到伤口闭合的显著延迟。此外，在USP15沉默的人真皮成纤维细胞中观察到细胞的增殖和迁移受到抑制。序列分析表明，USP15基因敲除后，转化生长因子-β(转化生长因子-β)途径受到抑制。此外，免疫共沉淀显示USP15可与转化生长因子-β受体I相互作用，促进其去泛素化，从而通过提高转化生长因子-β受体I的稳定性来维持转化生长因子-β信号通路的活性。这些观察结果阐明了USP15介导的转化生长因子-β信号通路在伤口愈合过程中的作用和机制，从而为难治性伤口的治疗提供了一个新的潜在靶点。
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, inUSP15knockout 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 afterUSP15knockdown. 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.