Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema.
Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema.
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DOI：
10.1007/s00109-011-0732-8
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发表时间：
2011-06
影响因子：
4.7
通讯作者：
Vij, Neeraj
中科院分区：
文献类型：
--
作者：
Min, Taehong;Bodas, Manish;Mazur, Steven;Vij, Neeraj
环境、遗传和/或年龄相关的蛋白质稳态变化会诱发炎症、氧化应激和细胞凋亡。我们使用来自对照和慢性阻塞性肺病 (COPD) 受试者（GOLD 0-IV 期）的肺组织样本以及香烟烟雾 (CS) 诱导的小鼠模型，量化了关键蛋白稳态介质的蛋白表达与慢性肺病严重程度的相关性。使用人支气管上皮细胞、HEK-293和Beas2B细胞进行体外实验来验证其机制。我们的数据验证了含缬洛新蛋白 (VCP) 逆行易位复合物 (VCP-Rma1-gp78) 的较高表达与 COPD 肺组织中肺气肿的严重程度以及炎症、内质网应激和细胞凋亡介质（如 NFκB、GADD-153/CHOP 和 p-eIF2α）的过度表达之间的相关性。此外，患有严重肺气肿的受试者泛素化蛋白和去泛素化酶 UCHL-1 的积累量较高，表明错误折叠或受损的蛋白质发生聚集。 CS 提取物对蛋白质降解和合成速率的调节证实了蛋白质稳态失衡在肺气肿和 COPD 中的发病作用。我们发现，VCP 还介导 HDAC2 和 Nrf2 的蛋白酶体降解，这是患有肺气肿的 COPD 受试者氧化应激和皮质类固醇抵抗增加的潜在机制。接下来，我们使用体外和小鼠模型证实较高的 VCP 表达与炎症和细胞凋亡增加相关。我们的数据清楚地显示患有严重肺气肿的慢性阻塞性肺病受试者存在异常的蛋白质稳态。此外，我们根据 Salubrinal（ER 应激抑制剂）控制 VCP 表达和泛素积累的能力来评估其纠正蛋白质稳态失衡的治疗效果。总的来说，我们的数据首次证明了蛋白质稳态失衡在严重肺气肿发病机制中的关键作用。
The environmental, genetic, and/or age-related changes in proteostasis induce inflammation, oxidative stress, and apoptosis. We quantified the correlation of protein expression of critical proteostasis mediators to severity of chronic lung disease using lung tissue samples from control and chronic obstructive pulmonary disease (COPD) subjects (GOLD stage 0–IV) and cigarette smoke (CS)-induced murine model. The human bronchial epithelial cells, HEK-293, and Beas2B cells were used for in vitro experiments to verify the mechanisms. Our data verifies the correlation of higher expression of valosin-containing protein (VCP) retrograde translocation complex (VCP-Rma1-gp78) with severity of emphysema in COPD lung tissues and over-expression of inflammatory, ER stress and apoptotic mediators like NFκB, GADD-153/CHOP, and p-eIF2α. Moreover, subjects with severe emphysema had a higher accumulation of ubiquitinated proteins and deubiquitinating enzyme, UCHL-1, indicating towards the aggregation of misfolded or damaged proteins. The modulation of both protein degradation and synthesis rates by CS-extract substantiates the pathogenetic role of proteostasis-imbalance in emphysema and COPD. We identified that VCP also mediates proteasomal degradation of HDAC2 and Nrf2, as a potential mechanism for increased oxidative stress and corticosteroid resistance in COPD subjects with emphysema. Next, we confirmed that higher VCP expression associates with increased inflammation and apoptosis using in vitro and murine models. Our data clearly shows aberrant proteostasis in COPD subjects with severe emphysema. In addition, we evaluate therapeutic efficacy of salubrinal (ER stress inhibitor) to correct the proteostasis-imbalance based on its ability to control VCP expression and ubiquitin accumulation. Overall, our data demonstrate for the first time the critical role of proteostasis-imbalance in pathogenesis of severe emphysema.
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