G2 and S phase-expressed protein 1 (GTSE1) has been implicated in the development of pulmonary fibrosis (PF); however, its biological function, molecular mechanism, and potential clinical implications remain unknown. Here, we explored the genomic data of patients with idiopathic PF (IPF) and found that GTSE1 expression is elevated in their lung tissues, but rarely expressed in normal lung tissues. Thus, we explored the biological role and downstream events of GTSE1 using IPF patient tissues and PF mouse models. The comprehensive bioinformatics analyses suggested that the increase of GTSE1 in IPF is linked to the enhanced gene signature for the epithelial-to-mesenchymal transition (EMT), leading us to investigate the potential interaction between GTSE1 and EMT transcription factors. GTSE1 preferentially binds to the less stable form of zinc-finger E-box-binding homeobox 1 (ZEB1), the unphosphorylated form at Ser585, inhibiting ZEB1 degradation. Consistently, the ZEB1 protein level in IPF patient and PF mouse tissues correlates with the GTSE1 protein level and the amount of collagen accumulation, representing fibrosis severity. Collectively, our findings highlight the GTSE1–ZEB1 axis as a novel driver of the pathological EMT characteristic during PF development and progression, supporting further investigation into GTSE1-targeting approaches for PF treatment.

中文翻译：

---

GTSE1 驱动的 ZEB1 稳定化通过上皮-间充质转化促进肺纤维化


G2 和 S 期表达蛋白 1 （GTSE1） 与肺纤维化 （PF） 的发生有关;然而，其生物学功能、分子机制和潜在的临床意义仍然未知。在这里，我们探索了特发性 PF （IPF） 患者的基因组数据，发现 GTSE1 表达在其肺组织中升高，但在正常肺组织中很少表达。因此，我们使用 IPF 患者组织和 PF 小鼠模型探讨了 GTSE1 的生物学作用和下游事件。全面的生物信息学分析表明，IPF 中 GTSE1 的增加与上皮-间充质转化 （EMT） 的增强基因特征有关，这促使我们研究 GTSE1 与 EMT 转录因子之间的潜在相互作用。GTSE1 优先与锌指 E 盒结合同源框 1 （ZEB1） 的不稳定形式结合，即 Ser585 位点的未磷酸化形式，抑制 ZEB1 降解。一致地，IPF 患者和 PF 小鼠组织中的 ZEB1 蛋白水平与 GTSE1 蛋白水平和胶原蛋白积累量相关，代表纤维化的严重程度。总的来说，我们的研究结果强调了 GTSE1-ZEB1 轴是 PF 发展和进展过程中病理 EMT 特征的新驱动因素，支持进一步研究 PF 治疗的 GTSE1 靶向方法。