2013/09/09

Ceramide-1-phosphate trafficking regulates intracellular eicosanoic lipid levels and the inflammation response

In the presence of harmful stimuli, intracellular production of eicosanoids triggers the pro-inflammatory response. However, chronic inflammation has obvious deleterious effects and it has been associated with different pathologies including asthma and cancer. For this reason, the precursor of eicosanoids, the arachidonic acid, is tightly regulated by several signalling molecules including the ceramide-1-phosphate (C1P). In a joint effort between the Memorial Sloan-Kettering Cancer Center, the University of Minnesota, the CIC bioGUNE and other institutions, the non-vesicular trafficking of C1P mediated by a human lipid transfer protein (CPTP) has been thoroughly investigated using a multidisciplinary approach. The high resolution structure, obtained by X-ray crystallography, identifies CPTP as the prototype for a new glycolipid transfer fold. Moreover, the crystal structures of CPTP with a plethora of lipidic substrates allowed unravelling the molecular basis for the selective recognition and binding among signalling lipids with phosphate head-groups. It is now clear that C1P binds through a novel surface localized site with a specific sub-site for the recognition of the phosphate head-group. Using a cleft-like mechanism, the interior part of the hydrophobic pocket of CPTP adaptatively expands to enclose a variety of lipids that differ in length. From the functional point of view, CPTP resides in the cytosol but associates with the trans-Golgi network, with the nucleus and with the plasma membrane. Depletion of CPTP levels using RNA interference raises the intracellular C1P concentration and alters the Golgi cisternae stack morphology. The abnormal levels of C1P generated trigger the release of arachidonic acid and, ultimately, the pro-inflammatory eicosanoid generation. The study has been published in Nature.

Link to the article:
http://www.ncbi.nlm.nih.gov/pubmed/23863933