Sphingolipid metabolic flow controls phosphoinositide turnover at the trans Golgi network

Sphingolipids are membrane lipids, which are globally required for eukaryotic life. Sphingolipid composition varies among endomembranes with pre- and post-Golgi compartments being poor and rich in sphingolipids, respectively. Thanks to this different sphingolipid content, pre- and post-Golgi membranes serve different cellular functions. Nevertheless, how subcellular sphingolipid levels are maintained in spite of trafficking and metabolic fluxes is only partially understood. Here we describe a homeostatic control circuit that controls sphingolipid levels at the trans Golgi network. Specifically, we show that sphingomyelin production at the trans Golgi network triggers a signalling reaction leading to PtdIns(4)P dephosphorylation. Since PtdIns(4)P is required for cholesterol, and sphingolipid transport to the trans Golgi network, PtdIns(4)P consumption leads to the interruption of this transport in response to excessive sphingomyelin production. Based on this evidence we envisage a model where this homeostatic circuit maintains the lipid composition of trans Golgi network and thus of post-Golgi compartments constant, against instant fluctuations in the sphingolipid biosynthetic flow.Peer ReviewedPostprint (author's final draft

Morphogenesis of post-Golgi transport carriers

The trans-Golgi network (TGN) is one of the main, if not the main, sorting stations in the process of intracellular protein trafficking. It is therefore of central importance to understand how the key players in the TGN-based sorting and delivery process, the post-Golgi carriers (PGCs), form and function. Over the last few years, modern morphological approaches have generated new insights into the questions of PGC biogenesis, structure and dynamics. Here, we present a view by which the “lifecycle” of a PGC consists of several distinct stages: the formation of TGN tubular export domains (where different cargoes are segregated from each other and from the Golgi enzymes); the docking of these tubular domains onto molecular motors and their extrusion towards the cell periphery along microtubules; the fission of the forming PGC from the donor membrane; and the delivery of the newly formed PGC to its specific acceptor organelle. It is now important to add the many molecular machineries that have been described as operating at the TGN to this “morphofunctional map” of the TGN export process

Presenilin 2 Modulates Endoplasmic Reticulum-Mitochondria Coupling by Tuning the Antagonistic Effect of Mitofusin 2

Communication between organelles plays key roles in cell biology. In particular, physical and functional coupling of the endoplasmic reticulum (ER) and mitochondria is crucial for regulation of various physiological and pathophysiological processes. Here, we demonstrate that Presenilin 2 (PS2), mutations in which underlie familial Alzheimer’s disease (FAD), promotes ER-mitochondria coupling only in the presence of mitofusin 2 (Mfn2). PS2 is not necessary for the antagonistic effect of Mfn2 on organelle coupling, although its abundance can tune it. The two proteins physically interact, whereas their homologues Mfn1 and PS1 are dispensable for this interplay. Moreover, PS2 mutants associated with FAD are more effective than the wild-type form in modulating ER-mitochondria tethering because their binding to Mfn2 in mitochondrial-associated membranes is favored. We propose a revised model for ER-mitochondria interaction to account for these findings and discuss possible implications for FAD pathogenesis