TRAF2 Is a Novel Ubiquitin E3 Ligase for the Na,K-ATPase β-Subunit That Drives Alveolar Epithelial Dysfunction in Hypercapnia.
TRAF2 Is a Novel Ubiquitin E3 Ligase for the Na,K-ATPase β-Subunit That Drives Alveolar Epithelial Dysfunction in Hypercapnia.
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TRAF2 是一种新型泛素 E3 连接酶，针对 Na,K-ATP 酶 β 亚基，可导致高碳酸血症中的肺泡上皮功能障碍。
DOI：
10.3389/fcell.2021.689983
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发表时间：
2021
影响因子：
5.5
通讯作者：
Vadász I
中科院分区：
文献类型：
--
作者：
Gabrielli NM;Mazzocchi LC;Kryvenko V;Tello K;Herold S;Morty RE;Grimminger F;Dada LA;Seeger W;Sznajder JI;Vadász I
一些急、慢性肺部疾病与肺泡通气量不足导致二氧化碳积聚(高碳酸血症)有关。Na，K-β酶的α亚基作为细胞黏附分子，调节转运蛋白催化的ATPase亚基的细胞表面稳定性，从而维持最佳的肺泡液平衡，在维持上皮细胞完整性方面起着关键作用。在这里，我们确定了Na，K-ATPaseβ亚基的E3泛素连接酶，当肺泡上皮细胞暴露在二氧化碳水平升高时，它促进了蛋白的多泛素化，随后的内吞作用和蛋白酶体的降解，从而损害了肺泡的完整性。Na，K-ATPaseβ-亚基的泛素化需要赖氨酸5和7，突变这些残基(而不是其他赖氨酸)可以阻止Na，K-ATPase从质膜上转运，并在高碳酸血症时稳定蛋白质。此外，Na，K-ATPaseβ-亚基的泛素化依赖于蛋白激酶C-ζ先前对丝氨酸11的磷酸化。利用蛋白质芯片，我们确定肿瘤坏死因子受体相关因子2(TRAF2)是在高碳酸血症时驱动Na，K-ATPaseβ-亚基泛素化的E3连接酶。值得注意的是，防止Na，K-ATPaseβ-亚基泛素化是必要的，也是在高二氧化碳条件下恢复细胞-细胞连接形成的充分条件。这些结果表明，肺内的高碳酸血症环境可能会导致受影响患者的持续性上皮功能障碍。因此，鉴定Na，K-ATPase的E3连接酶可能提供一个新的治疗靶点，用于急性或慢性高碳酸血症呼吸衰竭患者，旨在恢复肺泡上皮细胞的完整性。
Several acute and chronic lung diseases are associated with alveolar hypoventilation leading to accumulation of CO2 (hypercapnia). The β-subunit of the Na,K-ATPase plays a pivotal role in maintaining epithelial integrity by functioning as a cell adhesion molecule and regulating cell surface stability of the catalytic α-subunit of the transporter, thereby, maintaining optimal alveolar fluid balance. Here, we identified the E3 ubiquitin ligase for the Na,K-ATPase β-subunit, which promoted polyubiquitination, subsequent endocytosis and proteasomal degradation of the protein upon exposure of alveolar epithelial cells to elevated CO2 levels, thus impairing alveolar integrity. Ubiquitination of the Na,K-ATPase β-subunit required lysine 5 and 7 and mutating these residues (but not other lysines) prevented trafficking of Na,K-ATPase from the plasma membrane and stabilized the protein upon hypercapnia. Furthermore, ubiquitination of the Na,K-ATPase β-subunit was dependent on prior phosphorylation at serine 11 by protein kinase C (PKC)-ζ. Using a protein microarray, we identified the tumor necrosis factor receptor-associated factor 2 (TRAF2) as the E3 ligase driving ubiquitination of the Na,K-ATPase β-subunit upon hypercapnia. Of note, prevention of Na,K-ATPase β-subunit ubiquitination was necessary and sufficient to restore the formation of cell-cell junctions under hypercapnic conditions. These results suggest that a hypercapnic environment in the lung may lead to persistent epithelial dysfunction in affected patients. As such, the identification of the E3 ligase for the Na,K-ATPase may provide a novel therapeutic target, to be employed in patients with acute or chronic hypercapnic respiratory failure, aiming to restore alveolar epithelial integrity.
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影响因子：
7.3
作者：
Gwoździńska P;Buchbinder BA;Mayer K;Herold S;Morty RE;Seeger W;Vadász I
通讯作者：
Vadász I
影响因子：
6.4
作者：
Kundu, Samrat T.;Gosavi, Prajakta;Dalal, Sorab N.
通讯作者：
Dalal, Sorab N.
DOI：
10.1152/ajplung.00191.2013
发表时间：
2013-12-01
影响因子：
4.9
作者：
Grzesik, Benno A.;Vohwinkel, Christine U.;Vadasz, Istvan
通讯作者：
Vadasz, Istvan
影响因子：
5.3
作者：
Chadee, DN;Yuasa, T;Kyriakis, JM
通讯作者：
Kyriakis, JM
影响因子：
5.6
作者：
Laura Matos, Maria;Lapyckyj, Lara;Hebe Vazquez-Levin, Monica
通讯作者：
Hebe Vazquez-Levin, Monica