Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome.
Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome.
复制标题
2 型肺泡上皮细胞中的蛋白酶体功能障碍与急性呼吸窘迫综合征相关。
DOI：
10.1038/s41598-019-49020-4
复制
发表时间：
2019
影响因子：
4.6
通讯作者：
Weaver,TimothyE
中科院分区：
文献类型：
--
作者：
Sitaraman,Sneha;Na,Cheng-Lun;Yang,Li;Filuta,Alyssa;Bridges,JamesP;Weaver,TimothyE
蛋白酶体是质量控制的关键组成部分，调节短寿命，未折叠和错误折叠的蛋白质的周转。蛋白酶体活性已成为治疗目标，并被认为是包括肺纤维化在内的几种慢性肺部疾病的治疗选择。虽然对蛋白酶体活性的药理学抑制有效地阻止了成纤维细胞向肌成纤维细胞的转化，但对肺泡2型（AT2）上皮细胞的影响尚不清楚。为了解决这一知识差距，我们建立了一个遗传模型，在该模型中，促进活性26S蛋白酶体组装的蛋白酶体亚基RPT3在小鼠AT2细胞中被有条件地删除。RPT3的部分缺失导致26S蛋白酶体功能障碍，导致细胞应激增强和细胞死亡。AT2细胞的急性损失导致肺泡表面活性剂的消耗，肺泡上皮屏障的破坏，最终导致致命的急性呼吸窘迫综合征（ARDS）。这项研究强调了蛋白酶体功能在维持AT2细胞稳态中的重要性，并支持了进一步研究蛋白酶体功能障碍在ARDS发病机制中的作用的必要性。
Proteasomes are a critical component of quality control that regulate turnover of short-lived, unfolded, and misfolded proteins. Proteasome activity has been therapeutically targeted and considered as a treatment option for several chronic lung disorders including pulmonary fibrosis. Although pharmacologic inhibition of proteasome activity effectively prevents the transformation of fibroblasts to myofibroblasts, the effect on alveolar type 2 (AT2) epithelial cells is not clear. To address this knowledge gap, we generated a genetic model in which a proteasome subunit, RPT3, which promotes assembly of active 26S proteasome, was conditionally deleted in AT2 cells of mice. Partial deletion of RPT3 resulted in 26S proteasome dysfunction, leading to augmented cell stress and cell death. Acute loss of AT2 cells resulted in depletion of alveolar surfactant, disruption of the alveolar epithelial barrier and, ultimately, lethal acute respiratory distress syndrome (ARDS). This study underscores importance of proteasome function in maintenance of AT2 cell homeostasis and supports the need to further investigate the role of proteasome dysfunction in ARDS pathogenesis.