Alveolar enlargement is a pathological feature of emphysema. Long-term exposure to cigarette smoke (CS) is a high-risk factor for the development of emphysema. Abnormal protein ubiquitination has been implicated to regulate the development of human disorders, however, the role of protein ubiquitination in emphysema has not been well-studied. In this study, we attempted to investigate if a deubiquitinase, USP13, regulates the development of emphysema. Under a mild CS exposure condition, USP13-deficient mice show significant increases in alveolar chord length, indicating that USP13-deficient mice are susceptible to CS-induced alveolar enlargement. It has been shown that USP13 knockout reduced fibronectin expression in lungs. Here, we found that collagen levels were reduced in USP13 siRNA-transfected lung fibroblast cells. This suggests that a loss of extracellular matrix in connective tissues contributes to alveolar enlargement in USP13-deficient mice in response to CS exposure. Further, we investigated the role of USP13 in the expression of oxidative stress markers TXNIP and HMOX1. An increase in HMOX1 abundance was observed in USP13 knockdown lung fibroblast and epithelial cells. Overexpression of USP13 reduced HMOX1 protein levels in lung fibroblast cells, suggesting that modulation of USP13 levels may affect oxidative stress. Knockdown of USP13 significantly reduced TXNIP levels in lungs or lung fibroblast cells. A protein stability pulse-chase assay showed that TXNIP is instable within USP13 knockdown lung fibroblast cells. Further, the reduction of TXNIP was observed in USP13 inhibitor-treated lung epithelial cells. USP13-deficient mice also show higher levels of IgG in bronchoalveolar lavage fluid. This study provides evidence showing that USP13 deficiency plays a role in alveolar space enlargement.

中文翻译：

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USP13 缺乏会加剧香烟烟雾引起的肺泡空间扩大。

肺泡肿大是肺气肿的病理特征。长期接触香烟烟雾（CS）是发生肺气肿的高危因素。异常的蛋白质泛素化与调节人类疾病的发展有关，然而，蛋白质泛素化在肺气肿中的作用尚未得到充分研究。在这项研究中，我们试图调查去泛素酶 USP13 是否调节肺气肿的发展。在轻度CS暴露条件下，USP13缺陷型小鼠的肺泡弦长度显着增加，表明USP13缺陷型小鼠容易受到CS诱导的肺泡增大的影响。研究表明，USP13 敲除可降低肺中纤连蛋白的表达。在这里，我们发现 USP13 siRNA 转染的肺成纤维细胞中胶原蛋白水平降低。这表明结缔组织中细胞外基质的损失导致 USP13 缺陷小鼠响应 CS 暴露而出现肺泡扩大。此外，我们研究了 USP13 在氧化应激标志物 TXNIP 和 HMOX1 表达中的作用。在 USP13 敲低的肺成纤维细胞和上皮细胞中观察到 HMOX1 丰度增加。USP13 的过度表达降低了肺成纤维细胞中的 HMOX1 蛋白水平，表明 USP13 水平的调节可能会影响氧化应激。USP13 的敲低显着降低了肺或肺成纤维细胞中的 TXNIP 水平。蛋白质稳定性脉冲追踪测定表明 TXNIP 在 USP13 敲低的肺成纤维细胞内不稳定。此外，在 USP13 抑制剂处理的肺上皮细胞中观察到 TXNIP 的减少。USP13 缺陷小鼠的支气管肺泡灌洗液中也显示出较高水平的 IgG。这项研究提供的证据表明 USP13 缺乏在肺泡腔扩大中发挥作用。