Newly synthesized proteins and lipids are transported across the Golgi complex via different mechanisms whose respective roles are not completely clear. We previously identified a non-vesicular intra-Golgi transport pathway for glucosylceramide (GlcCer)—the common precursor of the different series of glycosphingolipids—that is operated by the cytosolic GlcCer-transfer protein FAPP2 (also known as PLEKHA8) (ref. 1). However, the molecular determinants of the FAPP2-mediated transfer of GlcCer from the cis-Golgi to the trans-Golgi network, as well as the physiological relevance of maintaining two parallel transport pathways of GlcCer—vesicular and non-vesicular—through the Golgi, remain poorly defined. Here, using mouse and cell models, we clarify the molecular mechanisms underlying the intra-Golgi vectorial transfer of GlcCer by FAPP2 and show that GlcCer is channelled by vesicular and non-vesicular transport to two topologically distinct glycosylation tracks in the Golgi cisternae and the trans-Golgi network, respectively. Our results indicate that the transport modality across the Golgi complex is a key determinant for the glycosylation pattern of a cargo and establish a new paradigm for the branching of the glycosphingolipid synthetic pathway.
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We thank A. Luini, C. Wilson and D. Priestman for discussions, A. Egorova for help with electron microscopy, G. Liebisch, A. Sigruener and G. Schmitz for lipidomic analysis. M.A.D.M. acknowledges the support of Telethon (GSP08002 and GGP06166), Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG 8623), and the EU (FP7 Lipidomicnet). G.D.’A. acknowledges the support of AIRC (MFAG 10585). P.M. acknowledges the support of Academy of Finland and Sigrid Jusélius Foundation. C.-C.C. was funded by a Study Abroad Scholarship from the Taiwan Ministry of Education.
The authors declare no competing financial interests.
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D’Angelo, G., Uemura, T., Chuang, CC. et al. Vesicular and non-vesicular transport feed distinct glycosylation pathways in the Golgi. Nature 501, 116–120 (2013). https://doi.org/10.1038/nature12423
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