14. Nonvesicular Trafficking of Ceramide-1-Phosphate By a Newly-Identified Lipid Transfer Protein That Regulates Eicosanoid Production. (original) (raw)

Nature, 2013

Abstract

"Phosphorylated sphingolipids ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P) have emerged as key regulators of cell growth, survival, migration and inflammation1–5. C1P produced by ceramide kinase is an activator of group IVA cytosolic phospholipase A2a (cPLA2a), the rate-limiting releaser of arachidonic acid used for pro-inflammatory eicosanoid production3,6–9, which contributes todisease pathogenesis in asthmaor airwayhyper-responsiveness, cancer, atherosclerosis and thrombosis.Tomodulate eicosanoid action and avoid the damaging effects of chronic inflammation, cells require efficient targeting, trafficking and presentation of C1P to specific cellular sites.Vesicular trafficking is likely10but non-vesicularmechanisms forC1Psensing, transfer andpresentation remain unexplored11,12. Moreover, the molecular basis for selective recognition and binding among signalling lipids with phosphate headgroups, namely C1P, phosphatidic acid or their lyso-derivatives, remains unclear. Here, a ubiquitously expressed lipid transfer protein, human GLTPD1, named here CPTP, is shown to specifically transfer C1P between membranes. Crystal structures establish C1P binding through a novel surface-localized, phosphate headgroup recognition centre connected to an interior hydrophobic pocket that adaptively expands to ensheath differing-length lipid chains using a cleft-like gating mechanism. The two-layer, a-helically-dominated ‘sandwich’ topology identifies CPTP as the prototype for a new glycolipid transfer protein fold13 subfamily.CPTPresides in the cell cytosol but associates with the trans- Golgi network, nucleus and plasma membrane. RNA interferenceinduced CPTP depletion elevates C1P steady-state levels and alters Golgi cisternae stack morphology. The resulting C1P decrease in plasma membranes and increase in the Golgi complex stimulates cPLA2a release of arachidonic acid, triggering pro-inflammatory eicosanoid generation."

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