A novel protein family controls trafficking and metabolism of glycosphingolipids (606.9)

Abstract

Glycosphingolipid (GSL) trafficking and metabolism are closely linked with cell fate determination, balancing signaling cascades controlling proliferation, apoptosis and autophagy. Altered cellular levels of complex glycosphingolipids often correlate with cancer progression, yet little is known about the principles that guide trafficking of these lipids.Here we identified a family of proteins, consisting of five mammalian homologues of the yeast Sfk1 protein that are involved in ganglioside transport. These six‐transmembrane domain proteins are widely expressed, each showing a unique cellular localization spanning the ER, Golgi, lysosomes and plasma membrane. One of these proteins, DNA‐damage regulated autophagy modulator 1 (DRAM1), was recently described as a p53‐inducible lysosomal regulator of autophagy. However, the cellular function(s) of the Sfk1 homologues remains unknown. Here we describe that mammalian Sfk1 proteins control the cellular distribution and metabolism of complex GSLs and one of them, DRAM2, specifically regulates transport of ganglioside GM3 from the plasma membrane to the Golgi and lysosomes. DRAM2‐mediated trafficking of GM3, in turn, was found to be critical for processing GM3 into higher ganglioside species.We propose that the Sfk1/DRAM family of proteins recognize GSLs within membranes and facilitate their sorting and hence their metabolic fate within the cell.Grant Funding Source: Supported by the NICHD Intramural research program