Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea.
Laboratory for Cellular Response to Oxidative Stress, Cell2in, Inc., Seoul 03127, Korea.
Int J Mol Sci. 2022 Feb 28;23(5):2709. doi: 10.3390/ijms23052709.
UV-irradiation induces the secretion of double-stranded RNA (dsRNA) derived from damaged noncoding RNAs in keratinocytes, which enhance the expression of matrix metalloproteinases (MMP) in non-irradiated dermal fibroblasts, leading to dysregulation of extracellular matrix homeostasis. However, the signaling pathway responsible for dsRNA-induced MMP expression has not been fully understood. Transglutaminase 2 (TG2) is an enzyme that modifies substrate proteins by incorporating polyamine or crosslinking of proteins, thereby regulating their functions. In this study, we showed that TG2 mediates dsRNA-induced MMP-1 expression through NF-κB activation. Treatment of poly(I:C), a synthetic dsRNA analogue binding to toll-like receptor 3 (TLR3), generates ROS, which in turn activates TG2 in dermal fibroblast. Subsequently, TG2 activity enhances translocation of p65 into the nucleus, where it augments transcription of MMP. We confirmed these results by assessing the level of MMP expression in , TG2-knockdowned and dermal fibroblasts after poly(I:C)-treatment. Moreover, treatment with quercetin showed dose-dependent suppression of poly(I:C)-induced MMP expression. Furthermore, ex vivo cultured skin from mice exhibited a significantly reduced level of MMP mRNA compared with those from wild-type mice. Our results indicate that TG2 is a critical regulator in dsRNA-induced MMP expression, providing a new target and molecular basis for antioxidant therapy in preventing collagen degradation.
紫外线照射会诱导角质细胞中非编码 RNA 损伤产生双链 RNA（dsRNA），进而增强未照射真皮成纤维细胞中基质金属蛋白酶（MMP）的表达，导致细胞外基质稳态失调。然而，dsRNA 诱导 MMP 表达的信号通路尚未完全阐明。转谷氨酰胺酶 2（TG2）是一种通过掺入多胺或蛋白质交联来修饰底物蛋白的酶，从而调节其功能。在本研究中，我们表明 TG2 通过 NF-κB 激活介导 dsRNA 诱导的 MMP-1 表达。聚肌苷酸（poly I:C）是一种与 Toll 样受体 3（TLR3）结合的合成 dsRNA 类似物，它会产生 ROS，进而激活真皮成纤维细胞中的 TG2。随后，TG2 活性增强 p65 向核内的易位，从而增强 MMP 的转录。我们通过评估 poly（I:C）处理后 TG2 敲低和 真皮成纤维细胞中 MMP 表达水平，证实了这些结果。此外，用槲皮素处理显示出对 poly（I:C）诱导的 MMP 表达的剂量依赖性抑制。此外，与野生型小鼠相比，从 小鼠体外培养的皮肤中 MMP mRNA 的水平明显降低。我们的结果表明，TG2 是 dsRNA 诱导的 MMP 表达的关键调节剂，为抗氧化治疗提供了一个新的靶点和分子基础，以防止胶原降解。
