Sphingosine 1-phosphate: The well-tempered bioactive lipid
Vascular Biology Program, Boston Children’s Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA
For classical music enthusiasts, Johann Sebastian Bach’s the well-tempered klavier represents a masterpiece that explores musical keys comprehensively in logical recurring patterns while achieving balance and harmony. As a student of bioactive lipids for almost three decades, my journey into the sphingosine 1-phosphate (S1P) research has revealed similar pleiotropic and repeating modules that ultimately achieves homeostasis of vertebrates. Originally recognized as a metabolic breakdown product of membrane sphingolipids by Stoffel in 1970s, the bioactivity of S1P was recognized in the 1990s by pioneers such as Gill, Spiegel and Igarashi, even though the prevailing notion at the time was that it acted as a second messenger. However, groups such as Moolenaar and Lynch and provided evidence for an extracellular G protein-coupled receptors (GPCR) for S1P, which ultimately proved to be correct. Our group attributes serendipity to our discovery of the vascular endothelial EDG-1 GPCR, which we ultimately proved to be the prototypical high-affinity GPCR for S1P (S1PR1). Five receptors (S1PR1-5) mediate multiple biological functions of S1P that impact all organ systems. A key unanswered question of the field is why a breakdown product of membrane sphingolipids is used in such a widespread manner in cell-cell communication events. Perhaps the unique physicochemical properties of S1P, such as resistance to oxidation, zwitterionic nature and limited aqueous solubility could provide partial answers. Indeed, several proteins that carry S1P in the extracellular environment and assist in its presentation to the GPCRs (termed as S1P chaperones), have evolved to fine tune its responses in different organ systems. For example, HDL-bound S1P induces vascular protection but not naïve T cell trafficking. Redundant S1P chaperones (albumin, ApoM, ApoA4) also allow plasticity of S1P function in various organ systems. Further work from the labs of Hannun, Obeid, Speigel, Igarashi and Proia have provided ample evidence for the critical intracellular role of S1P at the nexus of key metabolic pathways. Therefore, extracellular ligand and intracellular metabolic functions of S1P have been unequivocally established. Since biological systems possess built-in entropy and chaos, dysregulated S1P pathways play key roles in numerous disease processes. One might surmise that rational therapeutic development may not be straightforward for such a complex, multifunctional mediator. Again, serendipity ruled the day. FTY720, a derivative of a fungal metabolite was originally discovered by Fujita, Chiba and others as an immunosuppressant that inhibited autoreactive T cell trafficking. Suzanne Mandala and Kevin Lynch’s groups provided the key connection that this therapeutic modulated S1PRs. Cyster’s mechanistic studies in S1PR1 regulaton of lymphocyte trafficking further solidified this signaling mechanism in immunotherapy. However, dogged efforts by Brinkmann led to the approval of Fingolimod as a first oral disease-modifying therapeutic for the treatment of relapsing-remitting multiple sclerosis in 2010, thus providing clear utility for the S1P basic research into the clinical arena. Today, hundreds of thousands of patients with autoimmune diseases worldwide have benefited from S1P inhibitors. Many more drugs in the similar class are expected to be launched for several additional indications, including ulcerative colitis, psoriasis and systemic lupus erythematosus. While the current mainstream therapy targets lymphocyte S1PR1, addition therapeutic opportunities that target S1P metabolic enzymes, transporters and chaperones are envisioned for the benefit of human health. Thus, the logic of S1P signaling networks have revealed the intricate, recurring and comprehensive mechanisms that impact the biology of vertebrates as well as led to useful applications for human health.
Sphingosine phosphate lyase: from gene discovery to gene therapy
Division of Hematology/Oncology, UCSF, USA
Sphingosine phosphate lyase (SPL) is the vitamin B6-dependent enzyme responsible for the last step in the sphingolipid degradative pathway. SPL irreversibly cleaves sphingoid base phosphates — including the bioactive lipid sphingosine-1-phosphate (S1P) — producing a long chain aldehyde and ethanolamine phosphate. As the guardian of the only exit point for sphingolipid metabolism, SPL controls cellular levels of ceramides and other sphingolipid intermediates. The main features of SPL enzyme activity were first described in detail by Wilhelm Stoffel in 1969. The first SPL gene was identified in a yeast genetic screen thirty years later. In 2017, recessive mutations in the human SPL gene SGPL1 were recognized as the cause of sphingosine phosphate lyase insufficiency syndrome (SPLIS), a severe inborn error of metabolism with serious and often lethal consequences. Now, two targeted therapies for SPLIS are under investigation, namely vitamin B6 supplementation and SGPL1 gene therapy, the latter representing a potential universal cure for SPLIS.