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Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway

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 tha...

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Autores principales: 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 CM
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531943/
https://www.ncbi.nlm.nih.gov/pubmed/36102623
http://dx.doi.org/10.7554/eLife.79278
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author 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 CM
author_facet 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 CM
author_sort Sokoya, Tolulope
collection PubMed
description 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.
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spelling pubmed-95319432022-10-05 Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway 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 CM eLife Biochemistry and Chemical Biology 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. eLife Sciences Publications, Ltd 2022-09-14 /pmc/articles/PMC9531943/ /pubmed/36102623 http://dx.doi.org/10.7554/eLife.79278 Text en © 2022, Sokoya, Parolek et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
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 CM
Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway
title Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway
title_full Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway
title_fullStr Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway
title_full_unstemmed Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway
title_short Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway
title_sort pathogenic variants of sphingomyelin synthase sms2 disrupt lipid landscapes in the secretory pathway
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531943/
https://www.ncbi.nlm.nih.gov/pubmed/36102623
http://dx.doi.org/10.7554/eLife.79278
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