Abstract

Glycans are sugar polymers endowed with major biological functions. Their biosynthesis relies on orderly sequences of sugar additions catalysed by glycoenzymes during transport through the Golgi cisternae. How the position of glycoenzymes and hence their reaction sequence in the Golgi stack is determined to achieve the correct glycan output is unclear. Here, we address this question by studying the enzyme-recycling adaptor and oncogene GOLPH3 in the framework of the cisternal maturation, by which glycoenzymes recycle through progressing cisternae to maintain a suitable enzyme distribution across the Golgi stack. Our findings, unravel the mechanisms by which Golgi enzyme recycling specifies 1) the localization of specific glycoenzymes in the appropriate cisternae; 2) their degradation rate and hence their abundance; and 3) their organization into functional modules that impact specific glycosylation pathways and associated biological functions. Moreover, they have broad medical implications as they outline a novel oncogenic mechanism of action for GOLPH3 based on glycosphingolipid biosynthesis.