Magdaleno Carina, Tschumperlin Daniel J, Rajasekaran Narendiran, Varadaraj Archana
Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, AZ, USA.
Cancer Center, University of Arizona, Tucson, AZ, USA.
Sci Rep. 2024 Dec 30;14(1):31855. doi: 10.1038/s41598-024-83187-9.
Idiopathic pulmonary fibrosis (IPF) is a fatal disease defined by a progressive decline in lung function due to scarring and accumulation of extracellular matrix (ECM) proteins. The SOCS (Suppressor Of Cytokine Signaling) domain is a 40 amino acid conserved domain known to form a functional ubiquitin ligase complex targeting the Von Hippel Lindau (VHL) protein for proteasomal degradation. Here we show that the SOCS conserved domain operates as a molecular tool, to disrupt collagen and fibronectin fibrils in the ECM associated with fibrotic lung myofibroblasts. Our results demonstrate that fibroblasts differentiated using TGFβ, followed by transduction with the SOCS domain, exhibit significantly reduced levels of the contractile myofibroblast-marker, α-SMA. Furthermore, in support of its role to retard differentiation, we find that lung fibroblasts expressing the SOCS domain present with significantly reduced levels of α-SMA and fibrillar fibronectin after differentiation with TGFβ. We show that adenoviral delivery of the SOCS domain in the fibrotic phase of experimental lung fibrosis in mice, significantly reduces collagen accumulation in disease lungs. These data underscore a novel function for the SOCS domain and its potential in ameliorating pathologic matrix deposition in lung fibroblasts and experimental lung fibrosis.
特发性肺纤维化（IPF）是一种致命疾病，其特征是由于细胞外基质（ECM）蛋白的瘢痕形成和积累导致肺功能进行性下降。细胞因子信号转导抑制因子（SOCS）结构域是一个由40个氨基酸组成的保守结构域，已知其能形成功能性泛素连接酶复合物，靶向冯·希佩尔-林道（VHL）蛋白进行蛋白酶体降解。在此，我们表明SOCS保守结构域作为一种分子工具，可破坏与肺纤维化肌成纤维细胞相关的ECM中的胶原蛋白和纤连蛋白原纤维。我们的结果表明，经转化生长因子β（TGFβ）诱导分化后再用SOCS结构域转导的成纤维细胞，其收缩性肌成纤维细胞标志物α-平滑肌肌动蛋白（α-SMA）的水平显著降低。此外，为支持其延缓分化的作用，我们发现表达SOCS结构域的肺成纤维细胞在经TGFβ分化后，α-SMA和纤维状纤连蛋白的水平显著降低。我们表明，在小鼠实验性肺纤维化的纤维化阶段通过腺病毒递送SOCS结构域，可显著减少患病肺组织中的胶原蛋白积累。这些数据突显了SOCS结构域的新功能及其在改善肺成纤维细胞病理性基质沉积和实验性肺纤维化方面的潜力。
