Sphingolipid Transfer by GLTP-fold Proteins is Differentially Regulated by Phosphatidylinositol Derivatives

Immune response activation and localized cell suicide that halt the spread of pathogen infection in plants benefit from genetic models such as Arabidopsis accelerated-cell-death11 (acd11). In this mutant, depletion of ACD11, a lipid transfer protein that is specific for ceramide-1-phosphate (C1P) and phyto-C1P, disrupts sphingolipid homeo-stasis triggering programmed cell death. The C1P binding site in ACD11 and in human ceramide-1-phosphate transfer protein (CPTP) is surrounded by cationic residues. Here, we studied the regulation of C1P intermembrane transfer by ACD11 and CPTP when C1P-source vesicles contain various phosphatidylinositol (PI) derivatives (≤10 mol%) using Forster resonance energy transfer (FRET) involving anthrylvinyl and perylenoyl lipid probes. The presence and location of phosphate on the PI head group (PI-4P, PI-3P, PI-4,5P2) exerted differing effects on C1P transfer by ACD11 and CPTP. In contrast, none of the PI derivatives affected transfer action by human glycolipid lipid transfer protein (GLTP) which forms a glycolipid-specific GLTP-fold and has no cationic residue cluster near its glycolipid binding site. The findings provide evidence for the existence of a potential regulatory site for certain PI-derivatives on the surface C1P-specific, but not glycolipid-specific GLTP superfamily members. The results are discussed within the context of recent studies involving other anionic phosphoglycerides (phosphatidylglycerol, phosphatidylserine, phosphatidic acid) and these same sphingolipid transfer proteins. (Support: NIGMS GM45928; NHLBI HL125353; NCI CA121493; Russian Foundation for Basic Research 015-04-07415; Danish Strategic Research Council 09‑067148; Abby Rockefeller Mauze Trust; and the Maloris & Hormel Foundations.