In wound healing, the TG2 enzyme plays a dual functional role. TG2 has been shown to regulate extracellular matrix (ECM) stabilization by its transamidase activity while increasing cell migration by acting as a cell adhesion molecule. In this process, nitric oxide (NO) plays a particularly important role by nitrosylation of free cysteine ​​residues on TG2, leading to the irreversible inactivation of the catalytic activity.

In this study, transfected fibroblasts expressing TG2 under the control of the tetracycline-off promoter were treated with NO donor S-nitroso-N-acetyl penicillamine (SNAP) to analyze the interplay between NO and TG2 in the regulation of cell migration/invasion as well as TGF-β1-dependent MMP activation. Our results demonstrated that inhibition of TG2 cross-linking activity by SNAP promoted the migration and invasion capacity of fibroblasts by hindering TG2-mediated TGF-β1 activation. While the inhibition of TG2 activity by NO downregulated the biosynthesis and activity of MMP-2 and MMP-9, that of MMP-1a and MMP-13 was shown to be upregulated in a TGF-β1-dependent manner under the same conditions. In the presence of SNAP, interaction of TG2 with its cell surface binding partners Integrin-β1 and Syndecan-4 was reduced, which was paralleled by an increase in TG2 and PDGF association. These findings suggests that migratory phenotype of fibroblasts can be regulated by the interplay between nitric oxide and TG2 activity.

在伤口愈合中，TG2 酶具有双重功能。TG2 已显示通过其转酰胺酶活性调节细胞外基质 (ECM) 稳定性，同时通过充当细胞粘附分子增加细胞迁移。在这个过程中，一氧化氮（NO）通过将TG2上的游离半胱氨酸残基亚硝基化发挥着特别重要的作用，导致催化活性的不可逆失活。

在本研究中，用 NO 供体 S-亚硝基-N-乙酰青霉胺 (SNAP) 处理在四环素关闭启动子控制下表达 TG2 的转染成纤维细胞，以分析 NO 和 TG2 在调节细胞迁移/侵袭中的相互作用：以及 TGF-β1 依赖性 MMP 活化。我们的研究结果表明，SNAP 对 TG2 交联活性的抑制通过阻碍 TG2 介导的 TGF-β1 活化来促进成纤维细胞的迁移和侵袭能力。虽然 NO 对 TG2 活性的抑制下调了 MM​​P-2 和 MMP-9 的生物合成和活性，但 MMP-1a 和 MMP-13 在相同条件下以 TGF-β1 依赖性方式上调。在 SNAP 存在下，TG2 与其细胞表面结合伙伴 Integrin-β1 和 Syndecan-4 的相互作用减少，这与 TG2 和 PDGF 关联的增加平行。这些发现表明，成纤维细胞的迁移表型可以通过一氧化氮和 TG2 活性之间的相互作用来调节。