Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway
- Osnabrück University, Germany
- Danish Cancer Society, Denmark
- Université de Strasbourg, UMR 7021, CNRS, France
- University of Utah, United States
- Utrecht University, Netherlands
- University of Helsinki, Finland
- Yale University, United States
Abstract
Sphingomyelin is a dominant sphingolipid in mammalian cells. Its production in the trans-Golgi traps cholesterol synthesized in the ER to promote formation of a sphingomyelin/sterol gradient along the secretory pathway. This gradient marks a fundamental transition in physical membrane properties that help specify organelle identify and function. We previously identified mutations in sphingomyelin synthase SMS2 that cause osteoporosis and skeletal dysplasia. Here we show that SMS2 variants linked to the most severe bone phenotypes retain full enzymatic activity but fail to leave the ER owing to a defective autonomous ER export signal. Cells harboring pathogenic SMS2 variants accumulate sphingomyelin in the ER and display a disrupted transbilayer sphingomyelin asymmetry. These aberrant sphingomyelin distributions also occur in patient-derived fibroblasts and are accompanied by imbalances in cholesterol organization, glycerophospholipid profiles and lipid order in the secretory pathway. We postulate that pathogenic SMS2 variants undermine the capacity of osteogenic cells to uphold nonrandom lipid distributions that are critical for their bone forming activity.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file. Source Data files have been provided for Figures 2-4, 7-9 and Appendix 1 - figure 3.
Article and author information
Author details
Christopher G Burd
Funding
Deutsche Forschungsgemeinschaft (SFB944-P14)
- Joost CM Holthuis
Deutsche Forschungsgemeinschaft (HO3539/1-1)
- Joost CM Holthuis
Deutsche Forschungsgemeinschaft (SFB944-P8)
- Jacob Piehler
National Institutes of Health (R35 GM144096)
- Christopher G Burd
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Sokoya et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway
eLife 11:e79278.
https://doi.org/10.7554/eLife.79278
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