Sphingosine kinase 1 in viral infections

Abstract

Sphingosine kinase 1 (SphK1) is an enzyme that phosphorylates the lipid sphingosine to generate sphingosine-1-phosphate (S1P). S1P can act intracellularly as a signaling molecule and extracellularly as a receptor ligand. The SphK1/S1P axis has well-described roles in cell signaling, the cell death/survival decision, the production of a pro-inflammatory response, immunomodulation, and control of vascular integrity. Agents targeting the SphK1/S1P axis are being actively developed as therapeutics for cancer and immunological and inflammatory disorders. Control of cell death/survival and pro-inflammatory immune responses is central to the pathology of infectious disease, and we can capitalize on the knowledge provided by investigations of SphK1/S1P in cancer and immunology to assess its application to selected human infections. We have herein reviewed the growing literature relating viral infections to changes in SphK1 and S1P. SphK1 activity is reportedly increased following human cytomegalovirus and respiratory syncytial virus infections, and elevated SphK1 enhances influenza virus infection. In contrast, SphK1 activity is reduced in bovine viral diarrhea virus and dengue virus infections. Sphingosine analogs that modulate S1P receptors have proven useful in animal models in alleviating influenza virus infection but have shown no benefit in simian human immunodeficiency virus and lymphocytic choriomeningitis virus infections. We have rationalized a role for SphK1/S1P in dengue virus, chikungunya virus, and Ross River virus infections, on the basis of the biology and the pathology of these diseases. The increasing number of effective SphK1 and S1P modulating agents currently in development makes it timely to investigate these roles with the potential for developing modulators of SphK1 and S1P for novel anti-viral therapies.

Decreased plasma levels of the endothelial protective sphingosine-1-phosphate are associated with dengue-induced plasma leakage

“…S1P may also influence dengue pathogenesis in other ways. S1P has important effects on immune cell migration, release of inflammatory mediators, phagocytosis and cell death, as reviewed by Carr et al 34 and Maceyka et al 35 Specific data concerning alterations in sphingolipid metabolism in dengue infection are scarce. In vitro, reduced SphK1 in dengue-infected cells showed enhanced TNF-a induced apoptosis, 24 which could limit severe complications induced by pro-inflammatory cytokines and limit ongoing viral replication within infected cells.…”

Sphingosine kinase 1 (Sphk1) negatively regulates platelet activation and thrombus formation

“…Thus S1pr1-deficient megakaryocytes showed impaired migration of proplatelet extrusions in the circulatory compartment and impaired proplatelet shedding. Beyond that hematopoetic-specific knockout of S1pr1 leads to severe thrombocytopenia (19).In other cell types, S1P participates in the regulation of cell migration, proliferation, and cell adhesion (25, 37), as well as angiogenesis, atherosclerosis, and inflammation (11,23,37,43). Furthermore, S1P is heavily produced and secreted from activated platelets (53).…”

“…In other cell types, S1P participates in the regulation of cell migration, proliferation, and cell adhesion (25, 37), as well as angiogenesis, atherosclerosis, and inflammation (11,23,37,43). Furthermore, S1P is heavily produced and secreted from activated platelets (53).…”

A High-Throughput Genetic Complementation Assay in Yeast Cells Identified Selective Inhibitors of Sphingosine Kinase 1 Not Found Using a Cell-Free Enzyme Assay

“…9 SphK1 influences diverse cellular functions by regulating important cellular signaling pathways, including NF-kB, ERK/MAPK, and PI3K/ AKT. 2,[10][11][12] In addition, SphK1 is the predominant oncogenic isoform observed in human cancers 13,14 and its expression is elevated in stomach, lung, brain, colon, kidney, and breast cancers and non-Hodgkin lymphoma, 15 as well as in other cancers in which high tumor expression of SphK1 is correlated with decreased patient survival. [16][17][18] A recent report demonstrated that inhibition of SphK1 induced cell death in colon cancer cell lines and attenuated the serum-dependent PI3K/ AKT signaling and enhanced sensitivity of colon cancer cells to the chemotherapy drug, 5-fluorouracil.…”

“…POC, percent of control. Scatter plots comparing pIC 50 (-log10 [IC 50 ]) values determined from 10-point concentration-response testing of (A) 5,561 triaged IMAP HTS hits in SphK1 and SphK2 IMAP assays and (B) 78 selected IMAP HTS hits in SphK1 IMAP and microfluidic assays. The dashed lines show x = y. Potency of selected inhibitors and the optimized compound, C2, in the yeast and IMAP assays.…”