E4 engages uPAR and enolase-1 and activates urokinase to exert antifibrotic effects.
E4 engages uPAR and enolase-1 and activates urokinase to exert antifibrotic effects.
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DOI：
10.1172/jci.insight.144935
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发表时间：
2021-12-22
期刊：
影响因子：
8
通讯作者：
Feghali-Bostwick C
中科院分区：
文献类型：
--
作者：
Sharma S;Watanabe T;Nishimoto T;Takihara T;Mlakar L;Nguyen XX;Sanderson M;Su Y;Chambers RA;Feghali-Bostwick C
纤维增生性疾病，如系统性硬化症(SSC)，没有有效的治疗方法，导致显著的发病率和死亡率。我们最近证明，内皮抑素的C末端结构域，即E4，可以预防和逆转真皮和肺纤维化。我们的目标是确定E4消除纤维化的机制及其细胞表面结合伙伴(S)。我们的研究结果表明，E4激活了尿激酶途径，并增加了尿激酶型纤溶酶原激活物(UPA)与1型纤溶酶原激活物抑制物(PAI-1)的比率。此外，E4还显著增加了MMP1和MMP3的表达和活性。在体内，E4逆转了博莱霉素对PAI-1的诱导，并增加了uPA活性。SSc患者肺组织和肺成纤维细胞uPA/PAI-1比值均低于正常对照组。结合生物素E4的蛋白质被鉴定为烯醇化酶-1(ENO)和uPA受体(UPAR)。E4的抗纤维化作用需要uPAR。此外，eNO介导了转化生长因子-β-1的纤维化作用，并发挥了转化生长因子-β-1非依赖性的纤维化作用。我们的发现提示，E4的抗纤维化作用部分是通过调节尿激酶途径，以一种uPAR依赖的方式诱导基质金属蛋白酶-1和基质金属蛋白酶-3的水平和活性，从而促进细胞外基质的降解。此外，我们的发现确定了糖酵解酶ENO在纤维化中的兼职功能。
Fibroproliferative disorders such as systemic sclerosis (SSc) have no effective therapies and result in significant morbidity and mortality. We recently demonstrated that the C-terminal domain of endostatin, known as E4, prevented and reversed both dermal and pulmonary fibrosis. Our goal was to identify the mechanism by which E4 abrogates fibrosis and its cell surface binding partner(s). Our findings show that E4 activated the urokinase pathway and increased the urokinase plasminogen activator (uPA) to type 1 plasminogen activator inhibitor (PAI-1) ratio. In addition, E4 substantially increased MMP-1 and MMP-3 expression and activity. In vivo, E4 reversed bleomycin induction of PAI-1 and increased uPA activity. In patients with SSc, the uPA/PAI-1 ratio was decreased in both lung tissues and pulmonary fibroblasts compared with normal donors. Proteins bound to biotinylated-E4 were identified as enolase-1 (ENO) and uPA receptor (uPAR). The antifibrotic effects of E4 required uPAR. Further, ENO mediated the fibrotic effects of TGF-β1 and exerted TGF-β1–independent fibrotic effects. Our findings suggest that the antifibrotic effect of E4 is mediated, in part, by regulation of the urokinase pathway and induction of MMP-1 and MMP-3 levels and activity in a uPAR-dependent manner, thus promoting extracellular matrix degradation. Further, our findings identify a moonlighting function for the glycolytic enzyme ENO in fibrosis.
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影响因子：
6.5
作者：
Kanno, Yosuke;Kaneiwa, Aki;Matsuno, Hiroyuki
通讯作者：
Matsuno, Hiroyuki
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作者：
Hsu, Eileen;Shi, Haiwen;Jordan, Rick M.;Lyons-Weiler, James;Pilewski, Joseph M.;Feghali-Bostwick, Carol A.
通讯作者：
Feghali-Bostwick, Carol A.
影响因子：
6
作者：
Pilewski, JM;Liu, LX;Feghali-Bostwick, CA
通讯作者：
Feghali-Bostwick, CA