Sphingosine 1-phosphate lyase enhances the activation of IKKε to promote type I interferon-mediated innate immune response to influenza A virus infection

• Published in: The Journal of immunology (1950) 2017-06, Vol.199 (2), p.677-687
• Main Authors: Vijayan, Madhuvanthi, Xia, Chuan, Song, Yul Eum, Ngo, Hanh, Studstill, Caleb J., Drews, Kelly, Fox, Todd E., Johnson, Marc C., Hiscott, John, Kester, Mark, Alexander, Stephen, Hahm, Bumsuk
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601959

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.