Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Abstract

Sphingolipids are a diverse group of lipids that have essential cellular roles as structural components of membranes and as potent signaling molecules. In recent years, a detailed picture has emerged of the basic biochemistry of sphingolipids-from their initial synthesis in the endoplasmic reticulum (ER), to their elaboration into complex glycosphingolipids, to their turnover and degradation. However, our understanding of how sphingolipid metabolism is regulated in response to metabolic demand and physiologic cues remains incomplete. Here I discuss new insights into the mechanisms that ensure sphingolipid homeostasis, with an emphasis on the ER as a critical regulatory site in sphingolipid metabolism. In particular, Orm family proteins have recently emerged as key ER-localized mediators of sphingolipid homeostasis. A detailed understanding of how cells sense and control sphingolipid production promises to provide key insights into membrane function in health and disease.

Rom2-dependent Phosphorylation of Elo2 Controls the Abundance of Very Long-chain Fatty Acids

“…This in turn down-regulates Rom2 activity toward Rho1 and the downstream signaling cascade. Thus, both Rom2-dependent regulation of VLCFA and TORC2-dependent regulation of sphingosine synthesis respond to changes of the plasma membrane state (12). During myriocin treatment, TORC2 activity is increased, whereas Rom2 activity is decreased.…”

“…Although there are substantial differences in SLs between yeast and mammals (e.g. in the lipid headgroups), general aspects of SL metabolism, including key enzymes and regulatory features, are evolutionary conserved (12)(13)(14)(15)(16). As in metazoans, including humans, SL synthesis in yeast occurs in two branches that provide VLCFAs (saturated fatty acids containing 20 -26 carbon atoms) and sphingoid long-chain bases.…”

ORM Expression Alters Sphingolipid Homeostasis and Differentially Affects Ceramide Synthase Activities

“…The Saccharomyces cerevisiae Orm1p and Orm2p negatively regulate SPT through reversible phosphorylation of these polypeptides in response to intracellular sphingolipid levels (Breslow et al, 2010;Han et al, 2010;Roelants et al, 2011;Gururaj et al, 2013;Muir et al, 2014). Phosphorylation/dephosphorylation of ORMs in S. cerevisiae presumably affects the higher order assembly of SPT to mediate flux through this enzyme for LCB synthesis (Breslow, 2013). In this sphingolipid homeostatic regulatory mechanism, the S. cerevisiae Orm1p and Orm2p are phosphorylated at their N termini by Ypk1, a TORC2-dependent protein kinase Roelants et al, 2011).…”

Sphingolipid accumulation causes mitochondrial dysregulation and cell death

“…2,4 Cellular sphingolipid homeostasis is maintained by control of synthesis, breakdown and interorganellar transport of sphingolipid metabolites. 1 The importance of sphingolipids is underscored by several lysosomal storage disorders, including Tay Sachs, Gaucher and Nieman-Pick diseases, which are attributable to defective sphingolipid breakdown; similarly, a hereditary sensory neuropathy is caused by accumulation of abnormal sphingolipid metabolites. 5 Sphingolipids are regulated in response to metabolic need by the TOR signaling network that operates in two multiprotein complexes, TORC1 and TORC2.…”

“…1 Sphingolipid metabolites are also important signaling molecules linked to multiple other metabolic pathways with kinases and phosphatases as regulatory targets. 2,3 Sphingolipids have roles in numerous cell processes, including regulation of mitochondrial function, cell death and aging.…”