The Organization of the Sphingosine 1-Phosphate Signaling System

Rosen, Hugh; Sanna, Marta; Gonzalez-Cabrera, Pedro J.; Roberts, Edward

doi:10.1007/978-3-319-05879-5_1

Cited by 19 publications

(23 citation statements)

References 113 publications

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“…We demonstrated that S1P specifically interacts with (binds to) N-terminal domain of HSP90α. A specific binding site(s) of S1P to S1P receptors have been largely characterized (26). However, likewise TRAF2 and cIAP2, a specific interaction (binding) site(s) of S1P to HSP90s remains unknown.…”

Section: Identification Of Heat Shock Proteins In the S1p-mediated Simentioning

confidence: 99%

ER stress stimulates production of the key antimicrobial peptide, cathelicidin, by forming a previously unidentified intracellular S1P signaling complex

Park

Ikushiro

Seo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We recently identified a previously unidentified sphingosine-1-phosphate (S1P) signaling mechanism that stimulates production of a key innate immune element, cathelicidin antimicrobial peptide (CAMP), in mammalian cells exposed to external perturbations, such as UVB irradiation and other oxidative stressors that provoke subapoptotic levels of endoplasmic reticulum (ER) stress, independent of the well-known vitamin D receptor-dependent mechanism. ER stress increases cellular ceramide and one of its distal metabolites, S1P, which activates NF-κB followed by C/EBPα activation, leading to CAMP production, but in a S1P receptor-independent fashion. We now show that S1P activates NF-κB through formation of a previously unidentified signaling complex, consisting of S1P, TRAF2, and RIP1 that further associates with three stress-responsive proteins; i.e., heat shock proteins (GRP94 and HSP90α) and IRE1α. S1P specifically interacts with the N-terminal domain of heat shock proteins. Because this ER stress-initiated mechanism is operative in both epithelial cells and macrophages, it appears to be a universal, highly conserved response, broadly protective against diverse external perturbations that lead to increased ER stress. Finally, these studies further illuminate how ER stress and S1P orchestrate critical stress-specific signals that regulate production of one protective response by stimulating production of the key innate immune element, CAMP.ER stress | sphingosine-1-phosphate | heat shock protein 90 | cathelicidin | innate immunity

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Section: Identification Of Heat Shock Proteins In the S1p-mediated Simentioning

confidence: 99%

ER stress stimulates production of the key antimicrobial peptide, cathelicidin, by forming a previously unidentified intracellular S1P signaling complex

Park

Ikushiro

Seo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…SK1 has well-described functions in cell signalling, such as TNF-a-stimulated NFk B activation (Alvarez et al, 2010;Leclercq & Pitson, 2006;Maceyka et al, 2009;Xia et al, 2002), and in cell death/survival decisions (Pitson, 2011). The product of SK activity, S1P, can have intracellular signalling functions or be secreted from cells to act on cell surface S1P receptors (Leclercq & Pitson, 2006;Rosen et al, 2014;Spiegel & Milstien, 2011;Xia & Wadham, 2011). A number of studies have shown that modulating the S1P/receptor can reduce virus-induced disease and tissue injury associated with IAV (Marsolais et al, 2009;Walsh et al, 2011) and in an animal model of RSV infection (Walsh et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Reduction in sphingosine kinase 1 influences the susceptibility to dengue virus infection by altering antiviral responses

Clarke

Davies

Calvert

et al. 2016

Journal of General Virology

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Sphingosine kinase (SK) 1 is a host kinase that enhances some viral infections. Here we investigated the ability of SK1 to modulate dengue virus (DENV) infection in vitro. Overexpression of SK1 did not alter DENV infection; however, targeting SK1 through chemical inhibition resulted in reduced DENV RNA and infectious virus release. DENV infection of SK1 2/2 murine embryonic fibroblasts (MEFs) resulted in inhibition of infection in an immortalized line (iMEF) but enhanced infection in primary MEFs (18MEFs). Global cellular gene expression profiles showed expected innate immune mRNA changes in DENV-infected WT but no induction of these responses in SK1 2/2 iMEFs. Reverse transciption PCR demonstrated a low-level induction of IFN-b and poor induction of mRNA for the interferon-stimulated genes (ISGs) viperin, IFIT1 and CXCL10 in DENV-infected SK1 2/2 compared with WT iMEFs. Similarly, reduced induction of ISGs was observed in SK1 2/2 18MEFs, even in the face of high-level DENV replication. In both iMEFs and 18MEFs, DENV infection induced production of IFN-b protein. Additionally, higher basal levels of antiviral factors (IRF7, CXCL10 and OAS1) were observed in uninfected SK1 2/2 iMEFs but not 18MEFs. This suggests that, in this single iMEF line, lack of SK1 upregulates the basal levels of factors that may protect cells against DENV infection. More importantly, regardless of the levels of DENV replication, all cells that lacked SK1 produced IFN-b but were refractory to induction of ISGs such as viperin, IFIT1 and CXCL10. Based on these findings, we propose new roles for SK1 in affecting innate responses that regulate susceptibility to DENV infection.

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“…Sphingosine-1-phosphate (S1P) is a bioactive lipid which has been shown to exert important biological functions in a variety of systems such as the immune and cardiovascular systems as well as in the regulation of cancer cells [ 1 - 4 ]. S1P can function as a primary messenger to act on a family of five G-protein-coupled receptors (S1P receptors, S1PR 1–5 ) (reviewed by [ 5 , 6 ]). Several recent studies also demonstrate that S1P is involved in the sensation and modulation of pain (reviewed by [ 7 , 8 ]).…”

Section: Introductionmentioning

confidence: 99%

Sphingosine 1-phosphate enhances the excitability of rat sensory neurons through activation of sphingosine 1-phosphate receptors 1 and/or 3

Kays

et al. 2015

J Neuroinflammation

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BackgroundSphingosine-1-phosphate (S1P) is a bioactive sphingolipid that acts through a family of five G-protein-coupled receptors (S1PR1–5) and plays a key role in regulating the inflammatory response. Our previous studies demonstrated that rat sensory neurons express the mRNAs for all five S1PRs and that S1P increases neuronal excitability primarily, but not exclusively, through S1PR1. This raises the question as to which other S1PRs mediate the enhanced excitability.MethodsIsolated sensory neurons were treated with either short-interfering RNAs (siRNAs) or a variety of pharmacological agents targeted to S1PR1/R2/R3 to determine the role(s) of these receptors in regulating neuronal excitability. The excitability of isolated sensory neurons was assessed by using whole-cell patch-clamp recording to measure the capacity of these cells to fire action potentials (APs).ResultsAfter siRNA treatment, exposure to S1P failed to augment the excitability. Pooled siRNA targeted to S1PR1 and R3 also blocked the enhanced excitability produced by S1P. Consistent with the siRNA results, pretreatment with W146 and CAY10444, selective antagonists for S1PR1 and S1PR3, respectively, prevented the S1P-induced increase in neuronal excitability. Similarly, S1P failed to augment excitability after pretreatment with either VPC 23019, which is a S1PR1 and R3 antagonist, or VPC 44116, the phosphonate analog of VPC 23019. Acute exposure (10 to 15 min) to either of the well-established functional antagonists, FTY720 or CYM-5442, produced a significant increase in the excitability. Moreover, after a 1-h pretreatment with FTY720 (an agonist for S1PR1/R3/R4/R5), neither SEW2871 (S1PR1 selective agonist) nor S1P augmented the excitability. However, after pretreatment with CYM-5442 (selective for S1PR1), SEW2871 was ineffective, but S1P increased the excitability of some, but not all, sensory neurons.ConclusionsThese results demonstrate that the enhanced excitability produced by S1P is mediated by activation of S1PR1 and/or S1PR3.

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The Organization of the Sphingosine 1-Phosphate Signaling System

Cited by 19 publications

References 113 publications

ER stress stimulates production of the key antimicrobial peptide, cathelicidin, by forming a previously unidentified intracellular S1P signaling complex

ER stress stimulates production of the key antimicrobial peptide, cathelicidin, by forming a previously unidentified intracellular S1P signaling complex

Reduction in sphingosine kinase 1 influences the susceptibility to dengue virus infection by altering antiviral responses

Sphingosine 1-phosphate enhances the excitability of rat sensory neurons through activation of sphingosine 1-phosphate receptors 1 and/or 3

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