The Oncogene GOLPH3 regulates sphingolipid metabolism and cell proliferation
Glycans are abundant sugar polymers endowed with major biological functions. Their biosynthesis (also called glycosylation) relies on reactions catalyzed by hundreds of glycoenzymes (glycosyltransferases and glycosidases) organized in glycosylation pathways. Glycosylation depends on two factors: a) the expression patterns and catalytic properties of the glycoenzymes; and, b) the order and frequency of the reactions taking place between glycoenzymes and cargo protein or lipid substrates during transport through the Golgi. The reaction order determines the final glycan output, which typically consists of a limited set of functionally relevant cell- and protein-specific glycan chains.
How the position of glycoenzymes and hence their reaction sequence in the Golgi stack is determined to achieve the correct glycan output is unclear.
Using the oncogene and adaptor GOLPH3 as a tool, we have investigated the rules governing the localization of glycoenzymes in the Golgi stack and the assembly of glycans. We find that the Golgi, through the regulation of enzyme recycling mediated by GOLPH3 a) determines the localization of a subset of glycosphingolipid (GSL) biosynthetic enzymes in the appropriate Golgi cisternae; b) controls the abundance of specific GSL biosynthetic enzymes through the lysosomal degradation dependent process; and c) unexpectedly and importantly, organizes GSL glycoenzymes into functional adaptor-driven modules that operates in GSL synthesis. Specifically, when GOLPH3 is upregulated, enhances the production of bioactive GSLs at the expense of ceramide, a characterized tumor suppressor molecule, thus reprogramming the GSL pathway towards a pro-growth configuration.
These findings have broad medical implications as they outline a novel oncogenic mechanism of action for GOLPH3-induced proliferation based on glycosphingolipid biosynthesis.