Sphingosine 1-Phosphate Lyase Enhances the Activation of IKKε To Promote Type I IFN–Mediated Innate Immune Responses to Influenza A Virus Infection

Abstract

Sphingosine 1-phosphate (S1P) lyase (SPL) is an intracellular enzyme that mediates the irreversible degradation of the bioactive lipid, S1P. We have previously reported that overexpressed SPL displays anti-influenza viral activity; however the underlying mechanism is incompletely understood. In this study, we demonstrate that SPL functions as a positive regulator of IKKε to propel type I interferon (IFN)-mediated innate immune response against viral infection. Exogenous SPL expression inhibited influenza A virus (IAV) replication, which correlated with an increase in type I IFN production and interferon stimulated gene accumulation upon infection. In contrast, the lack of SPL expression led to an elevated cellular susceptibility to IAV infection. In support of this, SPL-deficient cells were defective in mounting an effective IFN response when stimulated by influenza viral RNAs. SPL augmented the activation status of IKKε, and enhanced the kinase-induced phosphorylation of IRF3 and synthesis of type I IFNs. However, S1P degradation-incompetent form of SPL also enhanced IFN responses, suggesting that SPL’s pro-IFN function is independent of S1P. Biochemical analysis revealed that SPL as well as the mutant form of SPL interact with IKKε. Importantly, when endogenous IKKε was down-regulated by an siRNA approach, SPL’s anti-influenza viral activity was markedly suppressed. This indicates that IKKε is crucial for SPL-mediated inhibition of influenza virus replication. Thus, the results illustrate the functional significance of the SPL-IKKε-IFN axis during host innate immunity against viral infection.

sNASP inhibits TLR signaling to regulate immune response in sepsis

“…IAV infection model. Influenza A/Puerto Rico/8/34 virus (IAV) infection and virus titer studies were performed as previously described (42). For the mortality studies, mice were infected by intranasal administration of 20,000 PFU IAV per mouse and monitored daily for up to 16 days.…”

Host sphingolipids: Perspective immune adjuvant for controlling SARS-CoV-2 infection for managing COVID-19 disease

“…Given S1P related pathogenic inflammation and association of S1PR1 and ACE2 linked signaling, it is likely that S1P, despite its antibacterial potential [ 29 ], might not be effective in controlling SARS-CoV-2 infection. Hence blocking S1P response either by enhancing S1P lyase activity [ 30 ] or inhibiting its binding to its receptor by use of analogue known as FTY720 (Fingolimod) [ 31 , 32 ] may modulate the pathogenesis of novel COVID-19 cases. Currently, FTY720 is being explored in the Phase-2 clinical trial against COVID-19 patients (NCT04280588, MRCTA, ECFAH of FMU), and results are still awaited.…”

Emerging Connections of S1P-Metabolizing Enzymes with Host Defense and Immunity During Virus Infections

“…The proposed cellular functions of SphK1 and SphK2 have similarities and distinct differences [29,30]. Intriguingly, the SphK isoforms and SPL have all been found to regulate virus propagation [31][32][33]. Furthermore, the levels and activation of SphK have been shown to be affected by several different viruses [34][35][36][37][38].…”

“…Importantly, the underlying mechanism of this resistance [33] indicates that SPL is a host-protective regulator that enhances the production of type I interferon (IFN) upon IAV infection or cellular recognition of influenza viral RNAs. This mechanism occurs through the interaction of SPL with inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε), a kinase important for IFN production.…”