Calmodulin Antagonizes a Calcium-Activated SCF Ubiquitin E3 Ligase Subunit, FBXL2, To Regulate Surfactant Homeostasis
Calmodulin Antagonizes a Calcium-Activated SCF Ubiquitin E3 Ligase Subunit, FBXL2, To Regulate Surfactant Homeostasis
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DOI：
10.1128/mcb.00723-10
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发表时间：
2011-05-01
影响因子：
5.3
通讯作者：
Mallampalli, Rama K.
中科院分区：
文献类型：
--
作者：
Chen, Bill B.;Coon, Tiffany A.;Mallampalli, Rama K.
钙调素是一种具有多效性的钙敏感蛋白。在这里，我们表明，钙调素抑制一个新的SCF（Skp 1-Cullin-F-box）E3连接酶的组成部分，FBXL 2。在铜绿假单胞菌感染期间，SCF（FBXL 2）靶向关键酶CCT α，用于其单泛素化和降解，从而减少不可或缺的膜和表面活性剂组分磷脂酰胆碱的合成。铜绿假单胞菌触发钙内流和高尔基复合体内FBXL 2的钙依赖性激活，在高尔基复合体中FBXL 2与CCT α结合。FBXL 2通过其C末端与CCT α IQ基序结合。FBXL 2敲低增加CCT α水平和磷脂合成。FBXL 2与CCT α的分子相互作用与钙调蛋白相反，钙调蛋白运输至高尔基复合体，通过其C末端结合FBXL 2（残基80至90），并与连接酶结合以占据IQ基序。这些观察结果在铜绿假单胞菌诱导的表面活性剂缺乏的小鼠模型中得到了重现，其中钙调蛋白基因转移通过稳定CCT α和减轻炎性肺损伤的严重程度来降低FBXL 2的作用。这些结果提供了一个独特的模型钙调节E3连接酶亚基和拮抗剂之间的分子间竞争，这是至关重要的肺炎和脂质稳态。
Calmodulin is a universal calcium-sensing protein that has pleiotropic effects. Here we show that calmodulin inhibits a new SCF (Skp1-Cullin-F-box) E3 ligase component, FBXL2. During Pseudomonas aeruginosa infection, SCF (FBXL2) targets the key enzyme, CCT alpha, for its monoubiquitination and degradation, thereby reducing synthesis of the indispensable membrane and surfactant component, phosphatidylcholine. P. aeruginosa triggers calcium influx and calcium-dependent activation of FBXL2 within the Golgi complex, where it engages CCT alpha. FBXL2 through its C terminus binds to the CCT alpha IQ motif. FBXL2 knockdown increases CCT alpha levels and phospholipid synthesis. The molecular interaction of FBXL2 with CCT alpha is opposed by calmodulin, which traffics to the Golgi complex, binds FBXL2 (residues 80 to 90) via its C terminus, and vies with the ligase for occupancy within the IQ motif. These observations were recapitulated in murine models of P. aeruginosa-induced surfactant deficiency, where calmodulin gene transfer reduced FBXL2 actions by stabilizing CCT alpha and lessening the severity of inflammatory lung injury. The results provide a unique model of calcium-regulated intermolecular competition between an E3 ligase subunit and an antagonist that is critically relevant to pneumonia and lipid homeostasis.