| First Author | Chen BB | Year | 2011 |
| Journal | Mol Cell Biol | Volume | 31 |
| Issue | 9 | Pages | 1905-20 |
| PubMed ID | 21343341 | Mgi Jnum | J:172833 |
| Mgi Id | MGI:5009099 | Doi | 10.1128/MCB.00723-10 |
| Citation | Chen BB, et al. (2011) Calmodulin antagonizes a calcium-activated SCF ubiquitin E3 ligase subunit, FBXL2, to regulate surfactant homeostasis. Mol Cell Biol 31(9):1905-20 |
| abstractText | 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, CCTalpha, 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 CCTalpha. FBXL2 through its C terminus binds to the CCTalpha IQ motif. FBXL2 knockdown increases CCTalpha levels and phospholipid synthesis. The molecular interaction of FBXL2 with CCTalpha 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 CCTalpha 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. |
