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Mol. Ther., Sep 27 2024, S1525-0016(24)00653-1 | https://doi.org/10.1016/j.ymthe.2024.09.029
GTSE1-driven ZEB1 Stabilization Promotes Pulmonary Fibrosis Through the Epithelial-to-mesenchymal Transition
Hee Jin 1†, So-Yeon Park 1,2†, Ji Eun Lee 1, Hangyeol Park 1, Michaela Jeong 1, Hyukjin Lee 1, Jaeho Cho 3, Yun-Sil Lee 1
1Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea
2Center for Genome Engineering, Institute for Basic Science, Daejeon, 34126, Republic of Korea
3Department of Radiation Oncology, Yonsei University Health System, Seoul 120-749, Republic of Korea
Corresponding author : Yun-Sil Lee
Abstract
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.
논문정보
- Research article
- 2024년 09월 (BRIC 등록일 2024-09-30)
- 국내 연구진
- 의약학 > 응용의학
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