biostudies-literatureRizzo RAssociazione Italiana per la Ricerca sul CancroStiftelsen Kristian Gerhard JebsenSwiss National Science FoundationNCI NIH HHSÉcole Polytechnique Fédérale de LausanneNIGMS NIH HHSe107238https://www.ebi.ac.uk/biostudies/studies/S-EPMC8047446biostudies-literatureUnknown40(8)Glycosphingolipids are important components of the plasma membrane where they modulate the activities of membrane proteins including signalling receptors. Glycosphingolipid synthesis relies on competing reactions catalysed by Golgi-resident enzymes during the passage of substrates through the Golgi cisternae. The glycosphingolipid metabolic output is determined by the position and levels of the enzymes within the Golgi stack, but the mechanisms that coordinate the intra-Golgi localisation of the enzymes are poorly understood. Here, we show that a group of sequentially-acting enzymes operating at the branchpoint among glycosphingolipid synthetic pathways binds the Golgi-localised oncoprotein GOLPH3. GOLPH3 sorts these enzymes into vesicles for intra-Golgi retro-transport, acting as a component of the cisternal maturation mechanism. Through these effects, GOLPH3 controls the sub-Golgi localisation and the lysosomal degradation rate of specific enzymes. Increased GOLPH3 levels, as those observed in tumours, alter glycosphingolipid synthesis and plasma membrane composition thereby promoting mitogenic signalling and cell proliferation. These data have medical implications as they outline a novel oncogenic mechanism of action for GOLPH3 based on glycosphingolipid metabolism.The EMBO journalGolgi maturation-dependent glycoenzyme recycling controls glycosphingolipid biosynthesis and cell growth via GOLPH3.PMC8047446Projects IG 15767P01 CA097132R35 GM118128IG 20786184926310030Institutional fundR01 CA218678Russo DVitagliano CSahu PMontariello DZito Marino FMandrich LHenklein PLuini AKunnathully VPothukuchi PParashuraman SMandel UPerez FKurokawa KZhukovsky MAVocat ABotti GCapolupo LHannun YAAquino GYamaji TCorda DLombardi BClausen HBoncompain GNakano ABudillon ASupino DD'Angelo GRizzo RHanada KfalseGolgi maturation-dependent glycoenzyme recycling controls glycosphingolipid biosynthesis and cell growth via GOLPH3.Glycosphingolipids are important components of the plasma membrane where they modulate the activities of membrane proteins including signalling receptors. Glycosphingolipid synthesis relies on competing reactions catalysed by Golgi-resident enzymes during the passage of substrates through the Golgi cisternae. The glycosphingolipid metabolic output is determined by the position and levels of the enzymes within the Golgi stack, but the mechanisms that coordinate the intra-Golgi localisation of the enzymes are poorly understood. Here, we show that a group of sequentially-acting enzymes operating at the branchpoint among glycosphingolipid synthetic pathways binds the Golgi-localised oncoprotein GOLPH3. GOLPH3 sorts these enzymes into vesicles for intra-Golgi retro-transport, acting as a component of the cisternal maturation mechanism. Through these effects, GOLPH3 controls the sub-Golgi localisation and the lysosomal degradation rate of specific enzymes. Increased GOLPH3 levels, as those observed in tumours, alter glycosphingolipid synthesis and plasma membrane composition thereby promoting mitogenic signalling and cell proliferation. These data have medical implications as they outline a novel oncogenic mechanism of action for GOLPH3 based on glycosphingolipid metabolism.2021-01-01T00:00:00Z2021 Apr2025-04-29T11:30:15.231Z2025-04-06T19:55:15.361ZS-EPMC80474463374989610.15252/embj.2020107238