Abstract
Sphingosine phosphate lyase (SPL) is the final enzyme in the sphingolipid degradative pathway, catalyzing the irreversible cleavage of long-chain base phosphates (LCBPs) to yield a long-chain aldehyde and ethanolamine phosphate (EP). SPL guards the sole exit point of sphingolipid metabolism. Its inactivation causes product depletion and accumulation of upstream sphingolipid intermediates. The main substrate of the reaction, sphingosine-1-phosphate (S1P), is a bioactive lipid that controls immune-cell trafficking, angiogenesis, cell transformation, and other fundamental processes. The products of the SPL reaction contribute to phospholipid biosynthesis and programmed cell-death activation. The main features of SPL enzyme activity were first described in detail by Stoffel et al. in 1969. The first SPL-encoding gene was cloned from budding yeast in 1997. Reverse and forward genetic strategies led to the rapid identification of other genes in the pathway and their homologs in other species. Genetic manipulation of SPL-encoding genes in model organisms has revealed the contribution of sphingolipid metabolism to development, physiology, and host-pathogen interactions. In 2017, recessive mutations in the human SPL gene SGPL1 were identified as the cause of a novel inborn error of metabolism associated with nephrosis, endocrine defects, immunodeficiency, acanthosis, and neurological problems. We refer to this condition as SPL insufficiency syndrome (SPLIS). Here, we share our perspective on the 50-year history of SPL from discovery to disease, focusing on insights provided by model organisms regarding the pathophysiology of SPLIS and how SPLIS raises the possibility of a hidden role for sphingolipids in other disease conditions.
Highlights
Sphingosine phosphate lyase (SPL) is the final enzyme in the sphingolipid degradative pathway, catalyzing the irreversible cleavage of long-chain base phosphates (LCBPs) to yield a long-chain aldehyde and ethanolamine phosphate (EP)
Degradation of LCBs involved an initial phosphorylation. We know that this step is catalyzed by sphingosine kinases and yields LCB phosphates (LCBPs), including the prolific bioactive lipid, sphingosine-1-phosphate (S1P), which ligates a family of G protein-coupled receptors [S1P receptors (S1PRs)] that play key roles in development, physiology, and immunology
Stoffel et al demonstrated that the enzyme responsible for the final cleavage reaction was enriched in the endoplasmic reticulum (ER) [2]
Summary
In Caenorhabditis elegans, silencing the SPL gene spl-1 results in semilethality, delayed development, and reproductive defects. Sgpl KO (SPL KO) mice accumulate sphingolipids, triglycerides, and cholesteryl esters [17] They exhibit lymphopenia, thymic atrophy, neutrophilia, anemia, nephrosis (excessive protein loss in the urine), increased cortical bone thickness, and rare developmental phenotypes often involving vascular structures [16,17,18,19,20]. Neural-specific SPL KO mice accumulate LCBs/LCBPs in the brain and exhibit deficits of spatial learning, memory, and motor function [24] These defects are accompanied by presynaptic pathology and reduced synaptic plasticity associated with a calcium-dependent induction of the unfolded protein response. Ichthiosis, immunodeficiency, cranial nerve palsies, bony abnormalities, hypocalcemia, gonadal defects, and other birth defects Another case of primary adrenal insufficiency caused by SGPL1 mutations was recently reported [34]. The fetal and perinatal deaths of the most severely affected SPLIS patients and the pleiotropic disease features provided a stark and unequivocal confirmation of the essential role SPL plays in human metabolism
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