Kohta Takahashi, Nario Tomishige, Mitsuhiro Abe, Gašper Šolinc, James Rae, Toshiyuki Yamaji, Frédéric Przybilla, Ludovic Richert, Nicolas Humbert, Takefumi Uemura, Thomas Wollert, Satoshi Waguri, Kentaro Hanada, Yasushi Sako, Gregor Anderluh, Robert G Parton, Yves Mély, Catherine Tomasetto, Fabien Alpy, Toshihide Kobayashi
The physiological role of lipid asymmetry in intracellular membranes remains poorly understood. Here, we show that sphingomyelin (SM), typically confined to the lumen of the trans-Golgi network (TGN), is exposed on its cytoplasmic surface by the action of the Golgi-associated protein, Golgi-associated gamma-adaptin ear-containing adenosine 5'-diphosphate-ribosylation factor-binding protein 1 (GGA1). This exposure is driven by the GGA1 GAT domain, which induces lipid scrambling in a manner dependent on membrane curvature and cholesterol. SM exposure coincides with the exit of mannose 6-phosphate receptors from the TGN, a process essential for lysosomal enzyme trafficking. Furthermore, SM is transferred to autophagic membranes, where it facilitates autophagosome-lysosome fusion. These findings reveal a previously unrecognized role for lipid remodeling in membrane trafficking and autophagy.