SPNS1 variants cause multiorgan disease and implicate lysophospholipid transport as critical for mTOR-regulated lipid homeostasis
Menglan He, Mei Ding, Michaela Chocholouskova, Cheen Fei Chin, Martin Engvall, Helena Malmgren, Matias Wagner, Marlen C. Lauffer, Jacob Heisinger, May Christine V. Malicdan, Valerie Allamand, Madeleine Durbeej, Angelica Delgado Vega, Thomas Sejersen, Ann Nordgren, Federico Torta, David L. Silver
Menglan He, Mei Ding, Michaela Chocholouskova, Cheen Fei Chin, Martin Engvall, Helena Malmgren, Matias Wagner, Marlen C. Lauffer, Jacob Heisinger, May Christine V. Malicdan, Valerie Allamand, Madeleine Durbeej, Angelica Delgado Vega, Thomas Sejersen, Ann Nordgren, Federico Torta, David L. Silver
View: Text | PDF
Research Article Cell biology Metabolism

SPNS1 variants cause multiorgan disease and implicate lysophospholipid transport as critical for mTOR-regulated lipid homeostasis

Abstract

SPNS1 is a lysosomal transporter that mediates the salvage of lysoglycerophospholipids, the degradative products of lysosomal phospholipid catabolism. However, an understanding of the role of lysolipid transport and salvage in regulating cellular lipid homeostasis and in disease is lacking. Here, we identified members of 2 families with biallelic SPNS1 loss-of-function variants, who presented primarily with progressive liver and striated muscle injury. Patients’ fibroblasts accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens. Notably, SPNS1 deficiency resulted in reduced biogenesis of cytosolic lipid droplets containing triglycerides and cholesteryl esters. Mechanistically, we found that lysophospholipids transported by SPNS1 into the cytosol quantitatively contributed to triglyceride synthesis, whereas lysosomal buildup of lyso-ether-phospholipid inhibited lysosomal cholesterol egress, effects that were enhanced with inhibition of mTOR. These findings support a gene-disease association and reveal connectivity between lysosomal transport of lysophospholipids and storage of reserve cellular energy as triglycerides and the regulation of cholesterol homeostasis, processes that become important under nutrient limitation.

Authors

Menglan He, Mei Ding, Michaela Chocholouskova, Cheen Fei Chin, Martin Engvall, Helena Malmgren, Matias Wagner, Marlen C. Lauffer, Jacob Heisinger, May Christine V. Malicdan, Valerie Allamand, Madeleine Durbeej, Angelica Delgado Vega, Thomas Sejersen, Ann Nordgren, Federico Torta, David L. Silver

×

Figure 5

PLA2G15 enzyme supplementation increases lysosomal cholesterol.

Options: View larger image (or click on image) Download as PowerPoint
PLA2G15 enzyme supplementation increases lysosomal cholesterol. HEK293T ...
HEK293T WT and SPNS1-KO cells were supplemented with 3 g/mL purified PLA2G15 for 48 hours, and plasma membrane cholesterol was depleted using MCD before harvesting cells for lipidomics analysis. (A) Heatmap representation of log2 fold change of lipid concentrations in SPNS1-KO and WT cells with or without PLA2G15 supplementation, and PLA2G15 SPNS1 double-KO (DKO) relative to SPNS1-KO cells. n = 3 replicates. P values were calculated using 2-tailed unpaired Student’s t tests and are presented in the Supplemental Data. (B–G) Cellular concentrations of LPC, LPE, LPC-O/P, LPE-P, and cholesterol and the sum of all lysophospholipids transported by SPNS1 (LPC, LPE, LPC-O/P, LPE-P). n = 3 replicates. Data are presented as the mean ± SD. Statistical significance was determined by 1way ANOVA with Šídák’s test.