Enzymes of Sphingolipid Metabolism:  From Modular to Integrative Signaling

Abstract

Many enzymes of sphingolipid metabolism are regulated in response to extra- and intracellular stimuli and in turn serve as regulators of levels of bioactive lipids (such as sphingosine, ceramide, sphingosine 1-phosphate, and diacylglycerol), and as such, they serve a prototypical modular function in cell regulation. However, lipid metabolism is also closely interconnected in that a product of one enzyme serves as a substrate for another. Moreover, many cell stimuli regulate more than one of these enzymes, thus adding to the complexity of regulation of lipid metabolism. In this paper, we review the status of enzymes of sphingolipid metabolism in cell regulation and propose a role for these enzymes in integration of cell responses, a role that builds on the modular organization while also taking advantage of the complexity and interconnectedness of lipid metabolism, thus providing for a combinatorial mechanism of generating diversity in cell responses. This may be a general prototype for the involvement of metabolic pathways in cell regulation.

A bacterial sulfonolipid triggers multicellular development in the closest living relatives of animals

“…Instead, we found that A. machipongonensis crude lipid extracts enriched in sphingolipids robustly induced rosette development (Figure 3A). In animals, sphingolipid signaling pathways regulate developmental processes such as cell death, survival, differentiation, and migration (Prieschl and Baumruker 2000; Pyne and Pyne 2000; Spiegel and Milstien 2000; Hannun et al 2001; Merrill et al 2001; Herr et al 2003). Moreover, sphingolipids serve essential functions both as structural components of cell membranes and as signaling molecules in diverse eukaryotes (Hannich et al 2011).…”

Steroidogenic factor-1 is a sphingolipid binding protein

“…However, over the past few decades, many studies have demonstrated that these molecules, notably ceramide and sphingosine-1-phosphate (S1P), play integral roles in mediating varied cellular processes (Hannun and Obeid, 2002;Igarashi et al, 2003;Merrill Jr. et al, 1997;Spiegel and Milstien, 2002;Spiegel and Milstien, 2003;Strasberg and Callahan, 1988;Tilly and Kolesnick, 2002;Vesper et al, 1999). Ceramide is a second messenger for events as diverse as differentiation, senescence, proliferation, cell cycle arrest, and apoptosis (Hannun, 1994;Hannun et al, 2001;Kolesnick, 2002). S1P also modulates a wide variety of physiological functions, including cell proliferation and survival (Castillo and Teegarden, 2001;Olivera and Spiegel, 1993;Olivera A et al, 1999;Spiegel and Milstien, 2002), chemotaxis (Hla et al, 1999), and in protection against ceramide-mediated apoptosis (Cuvillier et al, 1996).…”

The human T-cell leukemia virus type 1 p13II protein: effects on mitochondrial function and cell growth

“…These different effects are largely dependent on the activation status of the cell and on the concentration of the sphingolipids, which would thus act as a 'rheostat' that ultimately controls the balance between T-cell proliferation and death. 71,80,81 It is thus not surprising that, in addition to their increased sensitivity to C2-ceramide and FasL, Jurkat T cells expressing p13 II exhibit reduced proliferation rates compared to control cells, especially as they reach high cell densities. 34 This property could be indicative of the reaction of p13 II expressing cells to stress conditions (e.g.…”