期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 31, 期 9, 页码 1905-1920出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00723-10
关键词
-
资金
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development
- Department of Veterans Affairs
- NIH [R01, HL081784, HL096376, HL097376, HL098174]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据