在缺氧期间，磷酸化和泛素化对于钠钾ATP酶的内吞作用是必需的。
Phosphorylation and ubiquitination are necessary for Na,K-ATPase endocytosis during hypoxia.
作者信息
Dada Laura A, Welch Lynn C, Zhou Guofei, Ben-Saadon Ronen, Ciechanover Aaron, Sznajder Jacob I
机构信息
Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States.
出版信息
Cell Signal. 2007 Sep;19(9):1893-8. doi: 10.1016/j.cellsig.2007.04.013. Epub 2007 May 5.
Abstract
As a cellular adaptative response, hypoxia decreases Na,K-ATPase activity by triggering the endocytosis of its alpha(1) subunit in alveolar epithelial cells. Here, we present evidence that the ubiquitin conjugating system is important in the Na,K-ATPase endocytosis during hypoxia and that ubiquitination of Na,K-ATPase alpha(1) subunit occurs at the basolateral membrane. Endocytosis and ubiquitination were prevented when the Ser 18 in the PKC phosphorylation motif of the Na,K-ATPase alpha(1) subunit was mutated to an alanine, suggesting that phosphorylation at Ser-18 is required for ubiquitination. Mutation of the four lysines surrounding Ser 18 to arginine prevented Na,K-ATPase ubiquitination and endocytosis during hypoxia; however, only one of them was sufficient to restore hypoxia-induced endocytosis. We provide evidence that ubiquitination plays an important role in cellular adaptation to hypoxia by regulating Na,K-ATPase alpha(1)-subunit endocytosis.
摘要
作为一种细胞适应性反应，缺氧通过触发肺泡上皮细胞中Na，K - ATP酶α(1)亚基的内吞作用来降低其活性。在此，我们提供证据表明泛素结合系统在缺氧期间Na，K - ATP酶的内吞作用中起重要作用，并且Na，K - ATP酶α(1)亚基的泛素化发生在基底外侧膜。当Na，K - ATP酶α(1)亚基的PKC磷酸化基序中的丝氨酸18突变为丙氨酸时，内吞作用和泛素化被阻止，这表明丝氨酸18处的磷酸化是泛素化所必需的。将丝氨酸18周围的四个赖氨酸突变为精氨酸可防止缺氧期间Na，K - ATP酶的泛素化和内吞作用；然而，其中只有一个足以恢复缺氧诱导的内吞作用。我们提供证据表明，泛素化通过调节Na，K - ATP酶α(1)亚基的内吞作用在细胞对缺氧的适应中起重要作用。
相似文献
1
Phosphorylation and ubiquitination are necessary for Na,K-ATPase endocytosis during hypoxia.在缺氧期间，磷酸化和泛素化对于钠钾ATP酶的内吞作用是必需的。
Cell Signal. 2007 Sep;19(9):1893-8. doi: 10.1016/j.cellsig.2007.04.013. Epub 2007 May 5.
2
Hypoxia-induced endocytosis of Na,K-ATPase in alveolar epithelial cells is mediated by mitochondrial reactive oxygen species and PKC-zeta.缺氧诱导肺泡上皮细胞中钠钾ATP酶的内吞作用由线粒体活性氧和蛋白激酶C-ζ介导。
J Clin Invest. 2003 Apr;111(7):1057-64. doi: 10.1172/JCI16826.
3
Ubiquitination participates in the lysosomal degradation of Na,K-ATPase in steady-state conditions.在稳态条件下，泛素化参与钠钾ATP酶的溶酶体降解。
Am J Respir Cell Mol Biol. 2009 Dec;41(6):671-9. doi: 10.1165/rcmb.2008-0365OC. Epub 2009 Mar 13.
4
Alpha1-AMP-activated protein kinase regulates hypoxia-induced Na,K-ATPase endocytosis via direct phosphorylation of protein kinase C zeta.α1-AMP激活蛋白激酶通过直接磷酸化蛋白激酶C ζ调节缺氧诱导的钠钾ATP酶内吞作用。
Mol Cell Biol. 2009 Jul;29(13):3455-64. doi: 10.1128/MCB.00054-09. Epub 2009 Apr 20.
5
Phosphorylation of adaptor protein-2 mu2 is essential for Na+,K+-ATPase endocytosis in response to either G protein-coupled receptor or reactive oxygen species.衔接蛋白-2 μ2的磷酸化对于响应G蛋白偶联受体或活性氧的Na +，K + -ATP酶内吞作用至关重要。
Am J Respir Cell Mol Biol. 2006 Jul;35(1):127-32. doi: 10.1165/rcmb.2006-0044OC. Epub 2006 Feb 23.
6
Clathrin-mediated endocytosis of Na+,K+-ATPase in response to parathyroid hormone requires ERK-dependent phosphorylation of Ser-11 within the alpha1-subunit.网格蛋白介导的甲状旁腺激素刺激下的钠钾ATP酶内吞作用需要α1亚基中丝氨酸11的ERK依赖性磷酸化。
J Biol Chem. 2004 Apr 23;279(17):17418-27. doi: 10.1074/jbc.M311715200. Epub 2004 Feb 19.
7
HIF and HOIL-1L-mediated PKCζ degradation stabilizes plasma membrane Na,K-ATPase to protect against hypoxia-induced lung injury.低氧诱导因子（HIF）和 HOIL-1L 介导的蛋白激酶 Cζ（PKCζ）降解稳定质膜钠钾 ATP 酶，以防止低氧诱导的肺损伤。
Proc Natl Acad Sci U S A. 2017 Nov 21;114(47):E10178-E10186. doi: 10.1073/pnas.1713563114. Epub 2017 Nov 6.
8
Hypoxia-mediated degradation of Na,K-ATPase via mitochondrial reactive oxygen species and the ubiquitin-conjugating system.缺氧通过线粒体活性氧和泛素结合系统介导钠钾ATP酶的降解。
Circ Res. 2006 May 26;98(10):1314-22. doi: 10.1161/01.RES.0000222418.99976.1d. Epub 2006 Apr 13.
9
High CO2 Leads to Na,K-ATPase Endocytosis via c-Jun Amino-Terminal Kinase-Induced LMO7b Phosphorylation.高二氧化碳通过c-Jun氨基末端激酶诱导的LMO7b磷酸化导致钠钾ATP酶内吞作用。
Mol Cell Biol. 2015 Dec;35(23):3962-73. doi: 10.1128/MCB.00813-15. Epub 2015 Sep 14.
10
Regulation of Na,K-ATPase during acute lung injury.急性肺损伤期间钠钾ATP酶的调节
J Bioenerg Biomembr. 2007 Dec;39(5-6):391-5. doi: 10.1007/s10863-007-9102-1.
引用本文的文献
1
Sensing molecular carbon dioxide: a translational focus for respiratory disease.感知分子二氧化碳：呼吸系统疾病的转化研究重点
Physiol Rev. 2025 Oct 1;105(4):2657-2691. doi: 10.1152/physrev.00022.2024. Epub 2025 Jul 16.
2
Cell maturation influences the ability of hESC-RPE to tolerate cellular stress.细胞成熟会影响 hESC-RPE 耐受细胞应激的能力。
Stem Cell Res Ther. 2022 Jan 24;13(1):30. doi: 10.1186/s13287-022-02712-7.
3
Downregulation of RAB7 and Caveolin-1 increases MMP-2 activity in renal tubular epithelial cells under hypoxic conditions.在缺氧条件下，RAB7和小窝蛋白-1的下调会增加肾小管上皮细胞中MMP-2的活性。
Open Med (Wars). 2021 Sep 29;16(1):1428-1437. doi: 10.1515/med-2021-0341. eCollection 2021.
4
Regulatory effect of insulin on the structure, function and metabolism of Na/K-ATPase (Review).胰岛素对钠钾ATP酶结构、功能及代谢的调节作用（综述）
Exp Ther Med. 2021 Nov;22(5):1243. doi: 10.3892/etm.2021.10678. Epub 2021 Sep 1.
5
Crosstalk between phosphorylation and ubiquitination is involved in high salt-induced WNK4 expression.磷酸化与泛素化之间的相互作用参与了高盐诱导的WNK4表达。
Exp Ther Med. 2021 Feb;21(2):133. doi: 10.3892/etm.2020.9565. Epub 2020 Dec 10.
6
infection impairs chaperone-assisted maturation of Na-K-ATPase in gastric epithelium.感染会损害胃上皮细胞中天冬氨酸蛋白酶辅助成熟的伴侣。
Am J Physiol Gastrointest Liver Physiol. 2020 May 1;318(5):G931-G945. doi: 10.1152/ajpgi.00266.2019. Epub 2020 Mar 16.
7
Comparison of the adhesion and endocytosis of calcium oxalate dihydrate to HK-2 cells before and after repair by polysaccharide.多糖修复前后二水合草酸钙与HK-2细胞的黏附及内吞作用比较
Sci Technol Adv Mater. 2019 Nov 26;20(1):1164-1177. doi: 10.1080/14686996.2019.1697857. eCollection 2019.
8
DR region of Na-K-ATPase is a new target to protect heart against oxidative injury.钠钾 ATP 酶的 DR 区是保护心脏免受氧化损伤的新靶点。
Sci Rep. 2018 Aug 30;8(1):13100. doi: 10.1038/s41598-018-31460-z.
9
Ubiquitin-proteasome signaling in lung injury.泛素-蛋白酶体信号通路在肺损伤中的作用。
Transl Res. 2018 Aug;198:29-39. doi: 10.1016/j.trsl.2018.04.003. Epub 2018 Apr 23.
10
Hypoxia Activates Src and Promotes Endocytosis Which Decreases MMP-2 Activity and Aggravates Renal Interstitial Fibrosis.缺氧激活Src 并促进内吞作用，从而降低 MMP-2 活性并加重肾间质纤维化。
Int J Mol Sci. 2018 Feb 15;19(2):581. doi: 10.3390/ijms19020581.
本文引用的文献
1
Na,K-ATPase alpha1-subunit dephosphorylation by protein phosphatase 2A is necessary for its recruitment to the plasma membrane.蛋白磷酸酶2A使钠钾ATP酶α1亚基去磷酸化是其转运至质膜所必需的。
FASEB J. 2006 Dec;20(14):2618-20. doi: 10.1096/fj.06-6503fje. Epub 2006 Oct 25.
2
Phosphorylation of adaptor protein-2 mu2 is essential for Na+,K+-ATPase endocytosis in response to either G protein-coupled receptor or reactive oxygen species.衔接蛋白-2 μ2的磷酸化对于响应G蛋白偶联受体或活性氧的Na +，K + -ATP酶内吞作用至关重要。
Am J Respir Cell Mol Biol. 2006 Jul;35(1):127-32. doi: 10.1165/rcmb.2006-0044OC. Epub 2006 Feb 23.
3
Two different stages of epidermal growth factor (EGF) receptor endocytosis are sensitive to free ubiquitin depletion produced by proteasome inhibitor MG132.表皮生长因子（EGF）受体胞吞作用的两个不同阶段对蛋白酶体抑制剂MG132产生的游离泛素耗竭敏感。
Cell Biol Int. 2006 Jan;30(1):31-43. doi: 10.1016/j.cellbi.2005.09.003. Epub 2005 Nov 4.
4
Low density lipoprotein receptor-related protein 1 (LRP1) controls endocytosis and c-CBL-mediated ubiquitination of the platelet-derived growth factor receptor beta (PDGFR beta).低密度脂蛋白受体相关蛋白1（LRP1）控制血小板衍生生长因子受体β（PDGFRβ）的内吞作用和c-CBL介导的泛素化。
J Biol Chem. 2005 May 6;280(18):18504-10. doi: 10.1074/jbc.M410265200. Epub 2005 Mar 7.
5
Physiological and pathological responses to hypoxia.对缺氧的生理和病理反应。
Am J Pathol. 2004 Jun;164(6):1875-82. doi: 10.1016/S0002-9440(10)63747-9.
6
The internalization of yeast Ste6p follows an ordered series of events involving phosphorylation, ubiquitination, recognition and endocytosis.酵母Ste6p的内化遵循一系列有序事件，包括磷酸化、泛素化、识别和内吞作用。
Traffic. 2004 Mar;5(3):165-80. doi: 10.1111/j.1600-0854.2004.00168.x.
7
Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins.泛素及泛素结合蛋白对膜蛋白转运的调控
Annu Rev Cell Dev Biol. 2003;19:141-72. doi: 10.1146/annurev.cellbio.19.110701.154617.
8
Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation.受体酪氨酸激酶的多次单泛素化足以使其发生内吞作用并降解。
Nat Cell Biol. 2003 May;5(5):461-6. doi: 10.1038/ncb983.
9
Hypoxia-induced endocytosis of Na,K-ATPase in alveolar epithelial cells is mediated by mitochondrial reactive oxygen species and PKC-zeta.缺氧诱导肺泡上皮细胞中钠钾ATP酶的内吞作用由线粒体活性氧和蛋白激酶C-ζ介导。
J Clin Invest. 2003 Apr;111(7):1057-64. doi: 10.1172/JCI16826.
10
Signals for sorting of transmembrane proteins to endosomes and lysosomes.跨膜蛋白分选至内体和溶酶体的信号。
Annu Rev Biochem. 2003;72:395-447. doi: 10.1146/annurev.biochem.72.121801.161800. Epub 2003 Mar 6.
Zotero 插件