Sorting of lysosomal enzyme and autophagy are regulated by the GGA1-induced TGN lipid scrambling
Year: 2026
Type: article
Abstract: 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.
Source: Science Advances
Authors: 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
Institutions: Centre National de la Recherche Scientifique, Laboratoire de bioimagerie et pathologies, Université de Strasbourg, RIKEN, National Institute of Chemistry, The University of Queensland, Institute for Molecular Bioscience, Juntendo University, National Institute of Infectious Diseases, Fukushima Medical University, Institut Pasteur, Laboratoire de Biochimie, Biologie cellulaire physiologique et pathologique, Centre for Microscopy and Microanalysis, Inserm, Institut de génétique et de biologie moléculaire et cellulaire, Kyoto University of Advanced Science
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
OpenAlex ID: W7204565659