Sphingolipids as cell fate regulators in lung development and disease

Sphingolipids as cell fate regulators in lung development and disease Joyce Lee 0 1 Behzad Yeganeh 0 1 Leonardo Ermini 0 1 Martin Post 0 1 0 J. Lee M. Post Institute of Medical Science, University of Toronto , Toronto, ON , Canada 1 J. Lee B. Yeganeh L. Ermini M. Post (&) Program in Physiology and Experimental Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children , Toronto, ON M5G 0A4 , Canada Sphingolipids are a diverse class of signaling molecules implicated in many important aspects of cellular biology, including growth, differentiation, apoptosis, and autophagy. Autophagy and apoptosis are fundamental physiological processes essential for the maintenance of cellular and tissue homeostasis. There is great interest into the investigation of sphingolipids and their roles in regulating these key physiological processes as well as the manifestation of several disease states. With what is known to date, the entire scope of sphingolipid signaling is too broad, and a single review would hardly scratch the surface. Therefore, this review attempts to highlight the significance of sphingolipids in determining cell fate (e.g. apoptosis, autophagy, cell survival) in the context of the healthy lung, as well as various respiratory diseases including acute lung injury, acute respiratory distress syndrome, bronchopulmonary dysplasia, asthma, chronic obstructive pulmonary disease, emphysema, and cystic fibrosis. We present an overview of the latest findings related to sphingolipids and their metabolites, provide a short introduction to autophagy and apoptosis, and then briefly highlight the regulatory roles of sphingolipid metabolites in switching between cell survival and cell death. Finally, we describe functions of sphingolipids in autophagy and apoptosis in lung homeostasis, especially in the context of the aforementioned diseases. Ceramide; Sphingosine; Apoptosis; Caspase; Autophagy; Necroptosis; Lung development; Lung diseases - Abbreviations ALI Acute lung injury AMPK AMP-activated protein kinase Apaf-1 Apoptotic protease-activating factor-1 ARDS Acute respiratory distress syndrome aSMase Acid sphingomyelinase ATG Autophagy related genes BPD Bronchopulmonary dysplasia Caspase Cysteine aspartate-specific protease CF Cystic fibrosis CFTR Cystic fibrosis transmembrane conductance regulator CMA Chaperone-mediated autophagy COPD Chronic obstructive pulmonary disease DAPK Death-associated protein kinase DD Death domains DISC Death-inducing signaling complex ER Endoplasmic reticulum FasL Fas ligand FB1 Fumonisin B1 IPF Idiopathic pulmonary fibrosis JNK1 c-Jun NH2terminal kinase 1 LASS5 Longevity assurance homolog 5 LC3 Microtubule-associated protein 1 light chain 3 LPS Lipopolysaccharides MCRM Mitochondrial ceramide-rich macrodomain MLE Murine lung epithelial MOMP Mitochondrial outer membrane permeabilization mTOR Mammalian target of rapamycin mTORC1 mTOR complex 1 Sphingolipids are a class of lipids that were named after the mythological Sphinx because of their enigmatic nature. They were initially thought to serve strictly as structural components of the membrane bilayer, but have now been implicated in various cell-signaling pathways including cell proliferation, differentiation, and programmed cell death (PCD) [1]. These molecules display amphiphatic properties in which the hydrophobic end is comprised of a sphingoid base that is linked to a fatty acid, while the hydrophilic end varies in structures consisting of hydroxyl groups, phosphates and sugar residues. Different lengths, saturations, and hydroxylations of fatty acids, as well as different head groups result in an immense diversity of the sphingolipids species [2]. All sphingolipids can be generated from a derivation of ceramide. For example, as it is shown in Fig. 1, ceramide can be deacylated by ceramidase to sphingosine that then can be phosphorylated by a sphingosine kinase isoenzyme (SphK1 or SphK2) to form sphingosine-1-phosphate (S1P) [3, 4]. Alternatively, sphingosine can be acylated by ceramide synthase to give rise to ceramide. Both ceramide and sphingosine can act as a second messenger to promote apoptosis, cellular senescence, and growth arrest [5]. Sphingomyelin synthase converts ceramide to sphingomyelin, a structural lipid mainly localized to the outer membrane leaflet, while sphingomyelin can give rise to ceramide by the action of sphingomyelinase (SMase) isoenzymes [6]. Ceramide and S1P have received attention as they appear to play opposing roles in a dynamic relationship known as the sphingolipid rheostat [1, 7, 8]. At one end of the scale, ceramide is typically recognized to initiate apoptosis and growth arrest, whereas S1P, at the other end, promotes cell proliferation, survival, mobility, and cell-to-cell adhesion [911]. These two sphingolipids have been shown to play a role in cell fate processes such as apoptosis, and more recently, autophagy. A general overview of sphingolipid metabolism and their major functions is shown in Fig. 1. The role of sphingolipids in lung cell fate will be explored in this review. Ceramide can be generated through three known pathways. De novo synthesis of ceramide is characterized by the ratelimiting step of condensation between serine and palmitoylCoA catalyzed by serine palmitoyltransferase (SPT) [12]. Any of the sphingomyelinase isoenzymes, acid sphingomyelinase (aSMase), neutral sphingomyelinase (nSMase), and alkaline sphingomyelinase can use sphingomyelin as a substrate to produce ceramide [13]. Finally, synthesis of ceramide through a recycling loop from sphingosine and glycosphingolipids can also occur by the reverse activity of ceramidase [14]. Ceramide is a well-known critical mediator of various cell death pathways, including apoptosis and necrosis [15, 16]. Increased ceramide levels have been associated with apoptotic cell death in both homeostatic systems as well as pathological settings as a result of cellular insults including oxidative stress, chemotherapeutic agents, ischemia and radiation [5, 1720]. Studies investigating the mechanism of ceramide-mediated apoptosis have demonstrated that ceramide can act on both the intrinsic (mitochondrial) and extrinsic pathways of apoptosis in a context-dependent manner [21, 22]. Moreover, ceramide is able to induce apoptosis by recruitment of death receptors to lipid rafts and assembly of channels in the outer membrane of the mitochondria promoting the release of cytochrome c, only to mention a few amongst several investigated pathways [2224]. It has more recently been shown that ceramide has a significant impact on autophagy, influencing cellular fate under stress conditions such as amino acid deprivation, mitochondrial damage, and ER stress [2530]. S1P is well recognized to play critical roles in not only cell proliferation and survival, but also in cell mobility and Sphingomyelin Membrane structural lipid Fig. 1 Overview of sphingolipid metabolism and their majo (...truncated)