Sphingolipids: regulators of crosstalk between apoptosis and autophagy

Abstract

decades ago, pioneering work by Hannun et al. and Kolesnick et al. established the foundation for the bioactive nature of sphingolipids by demonstrating the inhibition of protein kinase C (PKC) by sphingosine and the stimulation of a ceramide-activated protein kinase in response to tumor necrosis factor (TNF)-␣ , respectively ( 1, 2 ). Sphingolipids have since been recognized as critical activators or inhibitors of various protein kinases and phosphatases, receptors, and ion transporters ( 3 ). Moreover, sphingolipids have been identifi ed as key regulators of a vast number of cellular processes, including cell growth, adhesion, migration, senescence, apoptosis, and most recently, autophagy ( 3, 4 ).Much of the investigation into sphingolipid signaling has focused on the disparate nature of ceramide and sphingosine-1-phosphate (S1P). Ceramide is typically associated with growth arrest and apoptosis, while S1P promotes cell proliferation and survival. The opposing nature and dynamic balance of intracellular ceramide and S1P, termed the "sphingolipid rheostat," has been proposed to determine cell fate ( 5 ). However, emerging evidence and extensive characterization of the sphingolipid metabolic network suggests that this two-dimensional model does not adequately refl ect sphingolipid signaling and function within the cell. In addition to ceramide and S1P, other sphingolipid metabolites, such as sphingosine, dihydroceramide, and gangliosides, have been implicated in the regulation of apoptosis and macroautophagy (hereafter referred to as autophagy). Although autophagy is typically considered to be a cytoprotective mechanism for the suppression of apoptosis, recent evidence indicates that autophagy can also promote cell death ( 6 ). Due to the differential regulation of apoptosis and autophagy by sphingolipid metabolites, the sphingolipid network has emerged as a novel molecular switch between the apoptotic and autophagic Abstract Apoptosis and autophagy are two evolutionarily conserved processes that maintain homeostasis during stress. Although the two pathways utilize fundamentally distinct machinery, apoptosis and autophagy are highly interconnected and share many key regulators. The crosstalk between apoptosis and autophagy is complex, as autophagy can function to promote cell survival or cell death under various cellular conditions. The molecular mechanisms of crosstalk are beginning to be elucidated and have critical implications for the treatment of various diseases, such as cancer. Sphingolipids are a class of bioactive lipids that mediate many key cellular processes, including apoptosis and autophagy. By targeting several of the shared regulators, sphingolipid metabolites differentially regulate the induction of apoptosis and autophagy. Importantly, individual sphingolipid species appear to "switch" autophagy toward cell survival (e.g., sphingosine-1-phosphate) or cell death (e.g., ceramide, gangliosides). This review assesses the current understanding of sphingolipid-induced apoptosis and autophagy to addr...

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