DC Field | Value | Language |
dc.contributor.author | Sokoya, Tolulope | |
dc.contributor.author | Parolek, Jan | |
dc.contributor.author | Foged, Mads Moller | |
dc.contributor.author | Danylchuk, I, Dmytro | |
dc.contributor.author | Bozan, Manuel | |
dc.contributor.author | Sarkar, Bingshati | |
dc.contributor.author | Hilderink, Angelika | |
dc.contributor.author | Philippi, Michael | |
dc.contributor.author | Botto, Lorenzo D. | |
dc.contributor.author | Terhal, Paulien A. | |
dc.contributor.author | Makitie, Outi | |
dc.contributor.author | Piehler, Jacob | |
dc.contributor.author | Kim, Yeongho | |
dc.contributor.author | Burd, Christopher G. | |
dc.contributor.author | Klymchenko, Andrey S. | |
dc.contributor.author | Maeda, Kenji | |
dc.contributor.author | Holthuis, Joost C. M. | |
dc.date.accessioned | 2023-02-17T11:36:54Z | - |
dc.date.available | 2023-02-17T11:36:54Z | - |
dc.date.issued | 2022 | |
dc.identifier.issn | 2050-084X | |
dc.identifier.uri | http://osnascholar.ub.uni-osnabrueck.de/handle/unios/65633 | - |
dc.description.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. | |
dc.description.sponsorship | Deutsche Forschungsgemeinschaft [SFB944-P14, HO3539/1-1, SFB944-P8]; National Institutes of Health [R35 GM144096]; Novo Nordisk Foundation [NNF17OC0029432]; Independent Research Fund Denmark [6108-00542B]; Deutsche Forschungsgemeinschaft SFB944-P14 Joost CM Holthuis Deutsche Forschungsgemeinschaft HO3539/1-1 JoostCM Holthuis Deutsche Forschungsgemeinschaft SFB944-P8 Jacob Piehler National Institutes of Health R35 GM144096 Christopher G Burd Novo Nordisk Foundation NNF17OC0029432 Kenji Maeda Independent Research Fund Denmark 6108-00542B Kenji Maeda The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. | |
dc.language.iso | en | |
dc.publisher | eLIFE SCIENCES PUBL LTD | |
dc.relation.ispartof | ELIFE | |
dc.subject | Biology | |
dc.subject | ENDOPLASMIC-RETICULUM | |
dc.subject | Human | |
dc.subject | Life Sciences & Biomedicine - Other Topics | |
dc.subject | lipid order probes | |
dc.subject | MACHINERY | |
dc.subject | MEMBRANE | |
dc.subject | organellar lipidomics | |
dc.subject | ORGANELLES | |
dc.subject | OSTEOGENESIS | |
dc.subject | osteoporosis | |
dc.subject | PHOSPHATIDYLSERINE | |
dc.subject | PROTEIN | |
dc.subject | sphingomyelin biosensor | |
dc.subject | transbilayer lipid asymmetry | |
dc.subject | TRANSBILAYER MOVEMENT | |
dc.subject | TRANSMEMBRANE DOMAINS | |
dc.subject | TRANSPORT | |
dc.title | Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway | |
dc.type | journal article | |
dc.identifier.doi | 10.7554/eLife.79278 | |
dc.identifier.isi | ISI:000864031300001 | |
dc.description.volume | 11 | |
dc.contributor.orcid | 0000-0002-1477-925X | |
dc.contributor.orcid | 0000-0001-8912-1586 | |
dc.contributor.orcid | 0000-0002-9080-5691 | |
dc.contributor.researcherid | G-2978-2018 | |
dc.publisher.place | SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND | |
dcterms.isPartOf.abbreviation | eLife | |
dcterms.oaStatus | gold, Green Submitted, Green Published | |
local.import.remains | affiliations : University Osnabruck; University Osnabruck; Danish Cancer Society; UDICE-French Research Universities; Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; University Osnabruck; Utah System of Higher Education; University of Utah; Utrecht University; Utrecht University Medical Center; University of Helsinki; University of Helsinki; Helsinki University Central Hospital; Yale University | |
local.import.remains | web-of-science-index : Science Citation Index Expanded (SCI-EXPANDED) | |
crisitem.author.dept | FB 05 - Biologie/Chemie | - |
crisitem.author.deptid | fb05 | - |
crisitem.author.orcid | 0000-0002-2143-2270 | - |
crisitem.author.parentorg | Universität Osnabrück | - |
crisitem.author.netid | PiJa938 | - |