Taleb Sarah J, Ye Qinmao, Baoyinna Boina, Dedad Michael, Pisini Dakshin, Parinandi Narasimham L, Cantley Lewis C, Zhao Jing, Zhao Yutong
Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
J Respir Biol Transl Med. 2024 Mar;1(1). doi: 10.35534/jrbtm.2024.10002. Epub 2024 Feb 1.
Thioredoxin-interacting protein (TXNIP) plays a critical role in regulation of cellular redox reactions and inflammatory responses by interacting with thioredoxin (TRX) or the inflammasome. The role of TXNIP in lung fibrosis and molecular regulation of its stability have not been well studied. Therefore, here we investigated the molecular regulation of TXNIP stability and its role in TGF-β1-mediated signaling in lung fibroblasts. TXNIP protein levels were significantly decreased in lung tissues from bleomycin-challenged mice. Overexpression of TXNIP attenuated transforming growth factor-β1 (TGF-β1)-induced phosphorylation of Smad2/3 and fibronectin expression in lung fibroblasts, suggesting that decrease in TXNIP may contribute to the pathogenesis of lung fibrosis. Further, we observed that TGF-β1 lowered TXNIP protein levels, while mRNA levels were unaltered by TGF-β1 exposure. TGF-β1 induced TXNIP degradation via the ubiquitin-proteasome system. A serine residue mutant (TNXIP-S308A) was resistant to TGF-β1-induced degradation. Furthermore, downregulationof ubiquitin-specific protease-13 (USP13) promoted the TGF-β1-induced TXNIP ubiquitination and degradation. Mechanistic studies revealed that USP13 targeted and deubiquitinated TXNIP. The results of this study revealed that the decrease of TXNIP in lungs apparently contributes to the pathogenesis of pulmonary fibrosis and that USP13 can target TXNP for deubiquitination and regulate its stability.
硫氧还蛋白相互作用蛋白（TXNIP）通过与硫氧还蛋白（TRX）或炎性小体相互作用，在细胞氧化还原反应和炎症反应的调节中发挥关键作用。TXNIP在肺纤维化中的作用及其稳定性的分子调控尚未得到充分研究。因此，我们在此研究了TXNIP稳定性的分子调控及其在肺成纤维细胞中转化生长因子-β1（TGF-β1）介导的信号传导中的作用。博来霉素诱导的小鼠肺组织中TXNIP蛋白水平显著降低。TXNIP的过表达减弱了TGF-β1诱导的肺成纤维细胞中Smad2/3的磷酸化和纤连蛋白的表达，表明TXNIP的减少可能促成肺纤维化的发病机制。此外，我们观察到TGF-β1降低了TXNIP蛋白水平，而mRNA水平不受TGF-β1暴露的影响。TGF-β1通过泛素-蛋白酶体系统诱导TXNIP降解。丝氨酸残基突变体（TNXIP-S308A）对TGF-β1诱导的降解具有抗性。此外，泛素特异性蛋白酶13（USP13）的下调促进了TGF-β1诱导的TXNIP泛素化和降解。机制研究表明，USP13靶向TXNIP并使其去泛素化。本研究结果表明，肺中TXNIP的减少显然促成了肺纤维化的发病机制，并且USP13可以靶向TXNP进行去泛素化并调节其稳定性。
