Title:	Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway
Authors:	Sokoya, Tolulope Parolek, Jan Foged, Mads Møller Danylchuk, Dmytro I. Bozan, Manuel Sarkar, Bingshati Hilderink, Angelika Philippi, Michael Botto, Lorenzo D. Terhal, Paulien A. Mäkitie, Outi Piehler, Jacob Kim, Yeongho Burd, Christopher G. Klymchenko, Andrey S. Maeda, Kenji Holthuis, Joost C. M.
ORCID of the author:	https://orcid.org/0000-0003-1831-8706 https://orcid.org/0000-0001-8912-1586 https://orcid.org/0000-0001-8426-369X https://orcid.org/0000-0002-4547-001X https://orcid.org/0000-0002-2143-2270 https://orcid.org/0000-0002-1477-925X
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.
Citations:	Tolulope Sokoya, Jan Parolek, Mads Møller Foged, Dmytro I Danylchuk, Manuel Bozan, Bingshati Sarkar, Angelika Hilderink, Michael Philippi, Lorenzo D Botto, Paulien A Terhal, Outi Mäkitie, Jacob Piehler, Yeongho Kim, Christopher G Burd, Andrey S Klymchenko, Kenji Maeda, Joost CM Holthuis (2022) Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway eLife 11:e79278
URL:	https://doi.org/10.48693/293 https://osnadocs.ub.uni-osnabrueck.de/handle/ds-202304198687
Subject Keywords:	sphingolipid; mammalian cells; Sphingomyelin synthase
Issue Date:	14-Sep-2022
License name:	Attribution 4.0 International
License url:	http://creativecommons.org/licenses/by/4.0/
Type of publication:	Einzelbeitrag in einer wissenschaftlichen Zeitschrift [Article]
Appears in Collections:	FB05 - Hochschulschriften Open-Access-Publikationsfonds

This item is licensed under a Creative Commons License