A ceramide sensor hiding in a family of sphingomyelin synthases (2024)

Geta Tafesse, F. (2009). A ceramide sensor hiding in a family of sphingomyelin synthases. [Doctoral thesis 1 (Research UU / Graduation UU), Utrecht University]. Utrecht University.

Geta Tafesse, F.. / A ceramide sensor hiding in a family of sphingomyelin synthases. Utrecht University, 2009. 136 p.

@phdthesis{0e645143893d440b90a85b78d9460214,

title = "A ceramide sensor hiding in a family of sphingomyelin synthases",

abstract = "Sphingolipids are vital components of cellular membranes that provide mechanical stability and play key roles in signal transduction, cell recognition and molecular sorting. They are synthesized from ceramide, a potent mediator of programmed cell death. Hence, cells face the dilemma of how to generate sufficient amounts of sphingolipids without killing themselves in the process. Ceramides are produced in the endoplasmic reticulum (ER) and transported to the Golgi for conversion to sphingomyelin (SM), the major sphingolipid in human cells. Cloning of the Golgi-resident SM synthase (SMS) uncovered a family of SMS enzymes. We found that one family member, SMSr, synthesizes the SM analogue ceramide phosphoethanolamine (CPE) in the ER. SMSr produces only trace amounts of CPE but blocking its catalytic activity causes a substantial rise in ER ceramide levels and triggers a mitochondrial pathway of apoptosis. SMSr-depleted cells become resistant to apoptosis upon disruption of ER-mitochondria contact sites or metabolic conversion of mitochondrial ceramides, indicating that apoptosis is triggered by mistargeting of ER ceramides to mitochondria. We also found that SMSr carries a SAM domain involved in polymeric protein-protein interactions. While SAM is dispensable for SMSr-catalysed CPE production, its removal proved sufficient to trigger ER ceramide accumulation and cell death. Our findings indicate that SMSr is an ER-resident ceramide sensor with a crucial role in protecting cells against ceramide-induced apoptosis. Since ceramide is intimately involved in the regulation of cancer cell-growth and survival, SMSr provides a legitimate target for modulating drug-induced cell death in tumors.",

author = "{Geta Tafesse}, F.",

year = "2009",

month = dec,

day = "14",

language = "Undefined/Unknown",

isbn = "978-90-393-5232-8",

publisher = "Utrecht University",

type = "Doctoral thesis 1 (Research UU / Graduation UU)",

school = "Utrecht University",

}

Geta Tafesse, F 2009, 'A ceramide sensor hiding in a family of sphingomyelin synthases', Doctor of Philosophy, Utrecht University.

A ceramide sensor hiding in a family of sphingomyelin synthases. / Geta Tafesse, F.
Utrecht University, 2009. 136 p.

Research output: Thesis › Doctoral thesis 1 (Research UU / Graduation UU)

TY - THES

T1 - A ceramide sensor hiding in a family of sphingomyelin synthases

AU - Geta Tafesse, F.

PY - 2009/12/14

Y1 - 2009/12/14

N2 - Sphingolipids are vital components of cellular membranes that provide mechanical stability and play key roles in signal transduction, cell recognition and molecular sorting. They are synthesized from ceramide, a potent mediator of programmed cell death. Hence, cells face the dilemma of how to generate sufficient amounts of sphingolipids without killing themselves in the process. Ceramides are produced in the endoplasmic reticulum (ER) and transported to the Golgi for conversion to sphingomyelin (SM), the major sphingolipid in human cells. Cloning of the Golgi-resident SM synthase (SMS) uncovered a family of SMS enzymes. We found that one family member, SMSr, synthesizes the SM analogue ceramide phosphoethanolamine (CPE) in the ER. SMSr produces only trace amounts of CPE but blocking its catalytic activity causes a substantial rise in ER ceramide levels and triggers a mitochondrial pathway of apoptosis. SMSr-depleted cells become resistant to apoptosis upon disruption of ER-mitochondria contact sites or metabolic conversion of mitochondrial ceramides, indicating that apoptosis is triggered by mistargeting of ER ceramides to mitochondria. We also found that SMSr carries a SAM domain involved in polymeric protein-protein interactions. While SAM is dispensable for SMSr-catalysed CPE production, its removal proved sufficient to trigger ER ceramide accumulation and cell death. Our findings indicate that SMSr is an ER-resident ceramide sensor with a crucial role in protecting cells against ceramide-induced apoptosis. Since ceramide is intimately involved in the regulation of cancer cell-growth and survival, SMSr provides a legitimate target for modulating drug-induced cell death in tumors.

AB - Sphingolipids are vital components of cellular membranes that provide mechanical stability and play key roles in signal transduction, cell recognition and molecular sorting. They are synthesized from ceramide, a potent mediator of programmed cell death. Hence, cells face the dilemma of how to generate sufficient amounts of sphingolipids without killing themselves in the process. Ceramides are produced in the endoplasmic reticulum (ER) and transported to the Golgi for conversion to sphingomyelin (SM), the major sphingolipid in human cells. Cloning of the Golgi-resident SM synthase (SMS) uncovered a family of SMS enzymes. We found that one family member, SMSr, synthesizes the SM analogue ceramide phosphoethanolamine (CPE) in the ER. SMSr produces only trace amounts of CPE but blocking its catalytic activity causes a substantial rise in ER ceramide levels and triggers a mitochondrial pathway of apoptosis. SMSr-depleted cells become resistant to apoptosis upon disruption of ER-mitochondria contact sites or metabolic conversion of mitochondrial ceramides, indicating that apoptosis is triggered by mistargeting of ER ceramides to mitochondria. We also found that SMSr carries a SAM domain involved in polymeric protein-protein interactions. While SAM is dispensable for SMSr-catalysed CPE production, its removal proved sufficient to trigger ER ceramide accumulation and cell death. Our findings indicate that SMSr is an ER-resident ceramide sensor with a crucial role in protecting cells against ceramide-induced apoptosis. Since ceramide is intimately involved in the regulation of cancer cell-growth and survival, SMSr provides a legitimate target for modulating drug-induced cell death in tumors.

M3 - Doctoral thesis 1 (Research UU / Graduation UU)

SN - 978-90-393-5232-8

PB - Utrecht University

ER -

Geta Tafesse F. A ceramide sensor hiding in a family of sphingomyelin synthases. Utrecht University, 2009. 136 p.