What is it about?

The lysosome is central to the degradation of proteins, sugars and lipids. Once broken down, these macromolecules are exported from lysosomes to the cytoplasm for reutilisation. The existence of dozens of lysosomal storage diseases highlights the crucial role that catabolism and export of lysosomal macromolecules play in cell and organ functions. Lysosomal transporters for amino acids, sugars and cholesterol have been identified, and the metabolic fates of these molecules in the cytoplasm have been elucidated. Remarkably, it was not known whether lysosomal salvage exists for glycerophospholipids, the major constituents of cellular membranes. In this paper, we hypothesised that a transporter exists for the efflux of lysophosphatidylcholine and lysophosphatidylethanolamine, the two lysosomal breakdown products of the most abundant cellular glycerophospholipids. Using a screening approach, we identified Spns1 as the lysosomal transporter for these lipid breakdown products and defined for the first time a phospholipid salvage pathway in which these specific lysophospholipids are exported from the lysosome by Spns1 are reutilised by the cell. We go on to demonstrate that Spns1 function is crucial for maintaining lysosomal function in cells, zebrafish and mouse liver.

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Why is it important?

The discovery that Spns1 is a lysosomal lysophospholipid transporter sets the stage to further elucidate the physiological and pathophysiological function of this particular phospholipid salvage pathway and more generally opens up opportunities to understand lysosomal lipid metabolism.

Perspectives

Historically, it has been difficult to identify lysosomal lipid transporters, limiting our understanding of the role of the lysosome in lipid metabolism and disease. This study provides a framework to investigate how this new transporter works and its role in health and disease.

David L Silver
Duke-NUS Medical School

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This page is a summary of: Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage, Proceedings of the National Academy of Sciences, September 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2210353119.
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