A ceramide sensor hiding in a family of sphingomyelin synthases

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

Cell biology : A brake on lipid synthesis

Although sphingolipids are vital cellular components, the path to their production is paved with toxic intermediates. Orm proteins allow cells to form these lipids without killing themselves in the proces

Comparison of infectivity of Plasmodium vivax to wild-caught and laboratory-adapted (colonized) Anopheles arabiensis mosquitoes in Ethiopia

Contains fulltext : 217316.pdf (publisher's version ) (Open Access

Tales and mysteries of the enigmatic sphingomyelin synthase family

In the last five years tremendous progress has been made toward the understanding of the mechanisms that govern sphingomyelin (SM) synthesis in animal cells. In line with the complexity of most biological processes, also in the case of SM biosynthesis, the more we learn the more enigmatic and finely tuned the system appears. Therefore with this review we aim first, at highlighting the most significant discoveries that advanced our knowledge and understanding of SM biosynthesis, starting from the discovery of SM to the identification of the enzymes responsible for its production; and second, at discussing old and new riddles that such discoveries pose to current investigator