Fifty years of lyase and a moment of truth: sphingosine phosphate lyase from discovery to disease

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.

Keywords: SGPL1; sphingolipids; sphingosine phosphate lyase insufficiency syndrome; sphingosine-1-phosphate.

Graphical abstract

Fig. 1.

Effects of 1 mM d-erythro-sphingosine on BST1/DPL1 overexpression and bst1/dpl1Δ yeast strains. Dilutions across are 0, 1:2, 1:4, 1:40, 1:400, and 1:4,000. Lanes 1–6 represent six different bst1/dpl1Δ strains. Lane 7 represents the BST1/DPL1 overexpression strain JS14. Lane 8 represents WT SGP3. Reproduced with permission from ref. .

Fig. 2.

Whole-mount survey of β-Gal-stained adult SPL reporter mouse organs. A: Whole brain. B: Olfactory bulb, showing staining of specific olfactory ganglia. C: Forebrain. D: Midbrain. E: Cerebellum and brainstem. F: Hindbrain. G: Basicranium, showing positively stained trigeminal nerve ganglia and unstained pituitary. H: Spinal cord, showing gray matter staining. I: Thymus and heart. Thymus is intensely stained. The pin is within the ventricular wall of the bisected heart, and the view shows the interior of the ventricle. J: Kidney, showing strong staining in the renal pelvis. K: Bladder, showing epithelial staining. L: Female gonads, including ovaries, fallopian tubes, and uterus. M: Foot. N: Skin. O: Preputial gland. P: Ribcage. Q: Liver. R: Stomach. S: Jejunum, with a Peyer’s patch in the center and showing less staining than the surrounding jejunal tissue. T: Ileum. U: Brown adipose tissue. V: Harderian gland and eye. W: Adrenal gland. X: Tail. Data are representative of results obtained from four animals (two male and two female). Reproduced with permission from ref. .

Fig. 3.

Gene trap disruption of the Sgpl1 gene causes S1P lyase deficiency. A: Sphingolipid metabolic pathway and linkage to triacylglycerol and PtdE synthesis. B: Appearance and life span of Sgpl1^−/−, Sgpl1^+/−, and Sgpl1^+/+ mice. Photo shows knockout mouse on the left and wild type mouse on the right. Reproduced with permission from ref. .

Fig. 4.

A: Homozygosity mapping and whole-exon sequencing reveal SGPL1 mutations as causing a human syndrome with nephrosis, ichthyosis, adrenal insufficiency, or neurologic defects and immunodeficiency. Some features of SPLIS include the following. B: Ptosis. C: Skin image showing brownish black desquamation on sebostatic skin with multipleradial papules with a blueish/black erythema and central calcinosis. D, E: Median and ulnar nerve paralysis. F: H&E-stained epidermal section showing acanthosis/orthokeratotic hyperkeratosis (black arrowhead) and calcinosis (white arrowhead). G: Renal histology (silver staining) showing focal segmental glomerulosclerosis. Scale bars: 100 μm. Reproduced with permission from ref. .