Thematic Review Series: Sphingolipids. ISC1 (inositol phosphosphingolipid-phospholipase C), the yeast homologue of neutral sphingomyelinases

Abstract

Sphingolipid biosynthesis and breakdown in yeast share many homologies in their pathways with higher eukaryotes (Dickson, R. C. 1998. Sphingolipid functions in Saccharomyces cerevisiae: comparison to mammals. Annu. . In mammals, ceramide can be generated through hydrolysis of sphingomyelin catalyzed by sphingomyelinase (SMase). To date, as many as five SMases have been identified molecularly, separated into three main groups: acid, alkaline, and neutral SMases (nSMases) (Marchesini, N., and Y. Hannun. 2004. Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem. Cell Biol. 82: 27-44). nSMase in mammals is represented by its homolog, inositol phosphosphingolipase C, codified by ISC1 in Saccharomyces cerevisiae (Sc) and Cryptococcus neoformans (Cn) and by CSS1 (Can't Stop Synthesizing cell wall) in Schizosaccharomyces pombe (Sp). Yeasts do not have sphingomyelin but instead have inositol phosphosphingolipids, which may function as orthologs of mammalian sphingomyelin. In this review, we will describe findings related to the function of ISC1, its localization, mechanisms, and its roles in cell response to different types of stresses. These studies serve as a foundation for the elucidation of the properties and functions of the extended family of nSMases. Ceramide has emerged as a highly studied bioactive and second-messenger lipid, with proposed roles in regulation of cell growth, cell death, senescence, and various stress responses (1, 2).A large number of enzymes are involved in regulating the levels of ceramide. To identify crucial enzymes that participate in the biochemical pathways leading to ceramide accumulation, many laboratories have focused on dissecting the biochemical pathways, and these studies have shown that ceramide can be produced in at least two distinct ways: the first is through the de novo pathway, which commences by the condensation of L-serine and palmitoyl-CoA, and the second by hydrolysis of complex lipids, especially sphingomyelin (3). The budding yeast, Saccharomyces cerevisiae (Sc), a fast-growing and genetically modifiable eukaryote, has been used extensively in elucidation of biochemical pathways of sphingolipid metabolism and functions of bioactive sphingolipids. In this review, we summarize findings about the enzyme that catalyzes the hydrolysis of yeast complex lipids to produce ceramide, ISC1 in Sc. We will also review other homologs of ISC1 in Schizosaccharomyces pombe (Sp), and the pathogen Cryptococcus neoformans (Cn), and then discuss implications for mammalian studies.Yeast and mammals share many similarities in sphingolipid metabolism (4), and these include the first two steps in the de novo pathway: synthesis of 3-ketodihydrosphingosine catalyzed by Lcb1p and Lcb2p in yeast, and by Sptlc1p and Sptlc2p in mammals. Lcb1p and Sptlc1p share 33% homology in their sequence, whereas Lcb2p and Sptlc2p have 48% sequence homology. These enzymes were first identified in yeast and later in mouse and human. The second step, characterized by the formation...

Identification and Characterization of Murine Mitochondria-associated Neutral Sphingomyelinase (MA-nSMase), the Mammalian Sphingomyelin Phosphodiesterase 5

“…This localization is notably different from all other mammalian N-SMases but, remarkably, is similar to what was previously reported for the yeast nSMase homologue ISC1, also a member of the extended N-SMase family. Interestingly, in S. cerevisiae, ISC1 localizes predominantly to the ER during exponential growth but appears to relocalize to the mitochondria following the diauxic shift, when metabolism switches from glycolytic to aerobic (31,32). With this in mind, it would be of great interest to determine whether the localization of MA-nSMase is also subject to such regulation.…”

Complementation of coenzyme Q‐deficient yeast by coenzyme Q analogues requires the isoprenoid side chain

“…If decylQ did not effectively upregulate mitochondrial [16]. Isc1 encodes a neutral sphingomyelinase that is localized to the endoplasmic reticulum and migrates to mitochondria during the diauxic shift [17]. Interestingly, the product of Isc1 is the signalling molecule ceramide, which has many structural similarities to CoQ [18].…”

Many Ceramides

“…These include molecular identification of enzymes of ceramide metabolism, development of in vivo models (e.g. yeast (11,25), Caenorhabditis elegans (26,27), Drosophila (28 -31), and genetically modified mice (32,33)) that have led to elucidation of key functions of various genes involved in ceramide metabolism, numerous cell biology advances that permitted defining several ceramide metabolism pathways, development of mass spectroscopy as a major analytical method to define and quantify ceramide and other sphingolipids (34,35), and the application of novel systems biology approaches to the study of sphingolipids (36). Unwittingly, these advances have highlighted previously unappreciated complexities of ceramide-regulated pathways, and these include the following.…”