Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673.
The Procter & Gamble Company, 8700 Mason-Montgomery Road, Cincinnati, OH 45040, USA.
Matrix Biol. 2023 Apr;118:110-128. doi: 10.1016/j.matbio.2023.03.004. Epub 2023 Mar 15.
Imbalance of collagen I expression results in severe pathologies. Apart from activation by the TGFβ-receptor/Smad pathway, control of collagen I expression remains poorly understood. Here, we used human dermal fibroblasts expressing a mCherry fluorescent protein driven by endogenous COL1A1 promoter to functionally screen the kinome and phosphatome. We identify 8 negative regulators, revealing that collagen is under tonic repression. The cell surface receptor BDKRB2 represses collagen I and other pro-fibrotic genes. Interestingly, it also promotes other basal membrane ECM genes. This function is independent of the natural ligand, bradykinin, and of SMAD2/3 factors, instead requiring constant ERK1/2 repression. TGFβ stimulation induces rapid BDKRB2 transcriptional downregulation. Human fibrotic fibroblasts have reduced BDKRB2 levels and enhancing its expression in keloid fibroblasts represses COL1A1. We propose that tonic signalling by BDKRB2 prevents collagen overproduction in skin fibroblasts.
胶原 I 表达失衡会导致严重的病理。除了被 TGFβ 受体/Smad 途径激活外，胶原 I 表达的调控仍知之甚少。在这里，我们使用表达 mCherry 荧光蛋白的人真皮成纤维细胞，通过内源性 COL1A1 启动子进行功能筛选激酶组和磷酸化组。我们鉴定出 8 个负调控因子，表明胶原处于紧张抑制状态。细胞表面受体 BDKRB2 抑制胶原 I 和其他促纤维化基因。有趣的是，它也促进其他基底膜 ECM 基因。该功能不依赖于天然配体缓激肽和 SMAD2/3 因子，而是需要持续抑制 ERK1/2。TGFβ 刺激诱导 BDKRB2 转录快速下调。人类纤维化成纤维细胞的 BDKRB2 水平降低，在瘢痕疙瘩成纤维细胞中增强其表达可抑制 COL1A1。我们提出，BDKRB2 的紧张信号可防止皮肤成纤维细胞胶原过度产生。
