Impact of pathogenic SMS2 variants on lipid landscapes and membrane properties along the secretory pathway

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Title: Impact of pathogenic SMS2 variants on lipid landscapes and membrane properties along the secretory pathway
Authors: Sokoya, Tolulope Tolu Victor
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Thesis advisor: Prof. Dr. Joost Holthuis
Thesis referee: Prof. Dr. Jacob Piehler
Abstract: Sphingomyelin (SM) is a major component of mammalian cell membranes. Its bulk production in the trans-Golgi provides a thermodynamic trap for cholesterol synthesized in the ER to promote the formation of a SM/sterol concentration gradient along the secretory pathway. This gradient marks a fundamental transition in physical membrane properties that helps specify organelle identity and function. A previous study identified mutations in SM synthase SMS2 as the underlying cause of a hereditary form of osteoporosis and skeletal dysplasia. This work shows that two missense SMS2 variants linked to the most severe bone phenotype, p.I62S and p.M64R, retain full enzymatic activity but are unable to leave the ER owing to a defective autonomous ER export signal. Consequently, bulk production of SM is mistargeted to the ER, the site for de novo synthesis of the SM precursor ceramide. Combining organellar lipidomics with the application of lipid reporters, I find that cells harboring these pathogenic SMS2 variants accumulate plasma membrane-like SM levels in the ER and display a disrupted SM asymmetry at the plasma membrane, presumably due to a constitutive SM scrambling in the ER. These aberrant SM distributions also occur in patient-derived fibroblasts and are accompanied by significant imbalances in cholesterol organization and lipid order along the secretory pathway. Moreover, I find that a more common nonsense SMS2 variant associated with a milder bone phenotype, p.R50X, yields a truncated but catalytically active enzyme that is mistargeted to an early Golgi compartment. Collectively, these data indicate that pathogenic SMS2 variants undermine the capacity of cells to uphold nonrandom lipid distributions in the secretory pathway that may be critical for the bone forming activity of osteogenic cells.
Subject Keywords: Cell Biology; Lipid biology; Sphingomyelin; Cholesterol; Lipid reporters
Issue Date: 28-Jun-2022
License name: Attribution 3.0 Germany
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Type of publication: Dissertation oder Habilitation [doctoralThesis]
Appears in Collections:FB05 - E-Dissertationen

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