PUBLICATION
Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage
- Authors
- He, M., Kuk, A.C.Y., Ding, M., Chin, C.F., Galam, D.L.A., Nah, J.M., Tan, B.C., Yeo, H.L., Chua, G.L., Benke, P.I., Wenk, M.R., Ho, L., Torta, F., Silver, D.L.
- ID
- ZDB-PUB-220929-15
- Date
- 2022
- Source
- Proceedings of the National Academy of Sciences of the United States of America 119: e2210353119 (Journal)
- Registered Authors
- Ho, Lena
- Keywords
- Mfsd2a, autophagy, lysosome, phospholipid, transporter
- MeSH Terms
-
- Animals
- Lysophosphatidylcholines/metabolism
- Lysophospholipids*/metabolism
- Lysosomes/metabolism
- Membrane Proteins
- Membrane Transport Proteins*/metabolism
- Mice
- Phosphatidylcholines/metabolism
- Phosphatidylethanolamines*/metabolism
- Protons
- Zebrafish*/metabolism
- Zebrafish Proteins
- PubMed
- 36161949 Full text @ Proc. Natl. Acad. Sci. USA
Citation
He, M., Kuk, A.C.Y., Ding, M., Chin, C.F., Galam, D.L.A., Nah, J.M., Tan, B.C., Yeo, H.L., Chua, G.L., Benke, P.I., Wenk, M.R., Ho, L., Torta, F., Silver, D.L. (2022) Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage. Proceedings of the National Academy of Sciences of the United States of America. 119:e2210353119.
Abstract
The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. 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 is not known whether lysosomal salvage exists for glycerophospholipids, the major constituents of cellular membranes. By using a transport assay screen against orphan lysosomal transporters, we identified the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter, with LPC and LPE being the lysosomal breakdown products of the most abundant eukaryotic phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively. Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species with pathological consequences on lysosomal function. Flux analysis using stable isotope-labeled phospholipid apolipoprotein E nanodiscs targeted to lysosomes showed that LPC was transported out of lysosomes in an Spns1-dependent manner and re-esterified back into the cytoplasmic pools of phosphatidylcholine. Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 and critical for maintaining normal lysosomal function.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping