Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids

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 (Fig. 1a) produced by ceramide kinase is an activator of group IVA cytosolic phospholipase A2α (cPLA2α), the rate-limiting releaser of arachidonic acid used for pro-inflammatory eicosanoid production3,6–9, which contributes to disease pathogenesis in asthma/airway hyper-responsiveness, cancer, atherosclerosis, and thrombosis. To modulate 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 likely10 but nonvesicular mechanisms for C1P sensing, transfer, and presentation remain unexplored11,12. Moreover, the molecular basis for selective recognition and binding among signaling lipids with phosphate headgroups, namely C1P, phosphatidic acid (PA) or their lyso-derivatives, remains unclear. Herein, an ubiquitously-expressed lipid transfer protein (CPTP) is shown to specifically transfer C1P between membranes. Crystal structures establish C1P binding via a novel surface-localized, phosphate headgroup recognition center connected to an interior hydrophobic pocket that adaptively expands to ensheath differing-length lipid chains using a cleft-like gating mechanism. The two-layer, α-helically-dominated ‘sandwich’ topology identifies CPTP as the prototype for a new GLTP-fold13 subfamily. CPTP resides in the cell cytosol but associates with the trans-Golgi/TGN, nucleus, and plasma membrane. RNAi-induced 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 cPLA2α release of arachidonic acid, triggering pro-inflammatory eicosanoid generation.

Profile of Dinshaw J. Patel

“…The structural data are consistent with a cleft-like conformational gating mechanism, whereby glycolipid chains sequentially enter and leave the molded-to-fit hydrophobic tunnel in the membrane-associated state during membrane vesicle biogenesis and trafficking (21).…”

Glucosylceramide Contained in Koji Mold-Cultured Cereal Confers Membrane and Flavor Modification and Stress Tolerance to Saccharomyces cerevisiae during Coculture Fermentation

“…Recent studies have shown that sphingolipids are synthesized through the membrane-trafficking system and transported across membranes by various mechanisms (9)(10)(11). Many single-celled eukaryotes (i.e., fungi and protists) contain both glucosylceramide (GlcCer) and inositolphosphoceramide (IPC) and their more complex metabolites.…”

Ceramide 1-Phosphate: A Mediator of Inflammatory Responses

“…Nonetheless, all of these effects of C1P may be cell-type specific, as C1P has also been associated to anti-inflammatory responses (Goggel et al 2004;Hankins et al 2011;Jozefowski et al 2010;Lamour et al 2011). The induction of pro-inflammatory responses by A-SMase-derived ceramides in pulmonary tissue and the inhibition of this enzyme by C1P have gained particular relevance with the recent discovery of a novel C1P transfer protein (CPTP) in human tissues (Simanshu et al 2013). It has been postulated that CPTP could transfer C1P to a site where it exerts an inhibitory effect on sphingomyelin degradation, a situation that is consistent with the reported inhibitory effect of C1P on lysosomal A-SMase (Gomez-Munoz et al 2004) and also with the inhibition of the de novo ceramide synthesis regulatory enzyme serine palmitoyltransferase (Granado et al 2009a), suggesting that these two enzymes may be important anti-inflammatory targets of C1P.…”