Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis

Abstract

Engagement of the Fas receptor (CD95) initiates multiple signaling pathways that lead to apoptosis, such as the formation of death-inducing signaling complex (DISC), activation of caspase cascades, and the generation of the lipid messenger, ceramide. Sphingomyelin (SM) is a major component of lipid rafts, which are specialized structures that enhance the efficiency of membrane receptor signaling and are a main source of ceramide. However, the functions of SM in Fas-mediated apoptosis have yet to be clearly defined, as the responsible genes have not been identified. After cloning a gene responsible for SM synthesis, SMS1, we established SM synthase–defective WR19L cells transfected with the human Fas gene (WR/Fas-SM(−)), and cells that have been functionally restored by transfection with SMS1 (WR/Fas-SMS1). We show that expression of membrane SM enhances Fas-mediated apoptosis through increasing DISC formation, activation of caspases, efficient translocation of Fas into lipid rafts, and subsequent Fas clustering. Furthermore, WR/Fas-SMS1 cells, but not WR/Fas-SM(−) cells, showed a considerable increase in ceramide generation within lipid rafts upon Fas stimulation. These data suggest that a membrane SM is important for Fas clustering through aggregation of lipid rafts, leading to Fas-mediated apoptosis.

Lipid signalling in disease

“…Ceramide can promote the clustering of death receptors 40 and interferes with the relay of PI3K signals by activating protein phosphatases, such as ceramide-activated protein phosphatase (CAPP) (FIG. 3).…”

Tales and Mysteries of the Enigmatic Sphingomyelin Synthase Family

“…[49][50][51][52][53] Recent evidence has further enriched this model supporting a role for SM in the homeostasis of lipid microdomains at the plasma membrane, often sites of receptor-mediated signaling. Taking advantage of the identification of SMS1 as bona fide SM synthase, the role of SM in the activation of Fas signaling was investigated by Miyaji et al 75 Comparing SMS1 deficient cells (with over expressed Fas receptor) with cells in which expression of SMS1 was restored, the authors provide evidence for a critical role of SM in Fas-mediated signaling by enabling the formation of the death-inducing signaling complex (DISC) and consequently allowing caspase activation and production of ceramide at the plasma membrane. Subsequently, the involvement of SMS1 in the maintenance of raft homeostasis has been postulated in S49 mouse lymphoma cells.…”

Caspase-mediated inhibition of sphingomyelin synthesis is involved in FasL-triggered cell death

“…27 Fas-mediated apoptosis was partly impaired in a murine leukemia cell line deficient in SMS, and overexpression of SMS1 restored full caspase activation and cell death. 28 Thus, a complete and sustained inhibition of SMS might alter membrane composition and properties through SM depletion and confer partial cell death resistance. 11 More recently, an overexpression of SMS1 or 2 in Chinese hamster ovarian cells enhanced TNF-induced apoptosis, whereas SMS1 or 2 knockdown in THP-1-derived macrophages was partially protective against cell death mediated by LPS.…”