Sorting of lysosomal enzyme and autophagy are regulated by the GGA1-induced TGN lipid scrambling
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.
Authors
- Satoshi Waguri (ORCID: https://orcid.org/0000-0001-9919-7111)
- Mitsuhiro Abe (ORCID: https://orcid.org/0000-0002-6244-1771)
- Gregor Anderluh (ORCID: https://orcid.org/0000-0002-9916-8465)
- Gašper Šolinc (ORCID: https://orcid.org/0000-0001-8243-0781)
- Frédéric Przybilla (ORCID: https://orcid.org/0009-0009-2016-353X)
- Robert G. Parton (ORCID: https://orcid.org/0000-0002-7494-5248)
- James Rae (ORCID: https://orcid.org/0000-0003-0525-2154)
- Yasushi Sako (ORCID: https://orcid.org/0000-0002-5707-5455)
- Nario Tomishige (ORCID: https://orcid.org/0000-0002-1266-5400)
- Kentaro Hanada (ORCID: https://orcid.org/0000-0003-1383-2781)
- Fabien Alpy (ORCID: https://orcid.org/0000-0002-0526-0720)
- Ludovic Richert (ORCID: https://orcid.org/0000-0003-4479-5418)
- Yves Mély (ORCID: https://orcid.org/0000-0001-7328-8269)
- Thomas Wollert (ORCID: https://orcid.org/0000-0001-9732-4789)
- Takefumi Uemura
- Toshihide Kobayashi (ORCID: https://orcid.org/0000-0002-4811-7270)
- Nicolas Humbert (ORCID: https://orcid.org/0000-0002-0166-5608)
- Toshiyuki Yamaji (ORCID: https://orcid.org/0000-0002-4251-489X)
- Kohta Takahashi (ORCID: https://orcid.org/0000-0001-9499-9035)
- Catherine Tomasetto
Institutions
- Centre National de la Recherche Scientifique (FR)
- Fukushima Medical University (JP)
- Inserm (FR)
- Institut Pasteur (FR)
- The University of Queensland (AU)
- National Institute of Infectious Diseases (JP)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Laboratoire de Biophotonique et Pharmacologie (FR)
- Tokyo Metropolitan Institute of Public Health (JP)
- RIKEN (JP)
- Takara (Japan) (JP)
- RIKEN Advanced Science Institute (JP)
- Juntendo University Urayasu Hospital (JP)
- National Institute of Chemistry (SI)
- Université de Strasbourg (FR)
- Kyoto University of Advanced Science (JP)
Publication Details
- Journal
- Science Advances
- Published
- 2026-08-28
- DOI
- https://doi.org/10.1126/sciadv.aec4519
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japanese Biochemical Society
- Agence Nationale de la Recherche
- Javna Agencija za Raziskovalno Dejavnost RS
- Australian Research Council
- RIKEN