tetano
Editor, Senior Moderator
J Immunol. 2017 Jun 9. pii: ji1601959. doi: 10.4049/jimmunol.1601959. [Epub ahead of print]
[h=1]Sphingosine 1-Phosphate Lyase Enhances the Activation of IKKε To Promote Type I IFN-Mediated Innate Immune Responses to Influenza A Virus Infection.[/h] Vijayan M[SUP]1,[/SUP][SUP]2[/SUP], Xia C[SUP]1,[/SUP][SUP]2[/SUP], Song YE[SUP]2[/SUP], Ngo H[SUP]1,[/SUP][SUP]2[/SUP], Studstill CJ[SUP]1,[/SUP][SUP]2[/SUP], Drews K[SUP]3[/SUP], Fox TE[SUP]4[/SUP], Johnson MC[SUP]2[/SUP], Hiscott J[SUP]5[/SUP], Kester M[SUP]4[/SUP], Alexander S[SUP]6[/SUP], Hahm B[SUP]7,[/SUP][SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 IFN-mediated innate immune responses against viral infection. Exogenous SPL expression inhibited influenza A virus replication, which correlated with an increase in type I IFN production and IFN-stimulated gene accumulation upon infection. In contrast, the lack of SPL expression led to an elevated cellular susceptibility to influenza A virus 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 the synthesis of type I IFNs. However, the S1P degradation-incompetent form of SPL also enhanced IFN responses, suggesting that SPL's pro-IFN function is independent of S1P. Biochemical analyses revealed that SPL, as well as the mutant form of SPL, interacts with IKKε. Importantly, when endogenous IKKε was downregulated using a small interfering RNA 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.
Copyright ? 2017 by The American Association of Immunologists, Inc.
PMID: 28600291 DOI: 10.4049/jimmunol.1601959
[h=1]Sphingosine 1-Phosphate Lyase Enhances the Activation of IKKε To Promote Type I IFN-Mediated Innate Immune Responses to Influenza A Virus Infection.[/h] Vijayan M[SUP]1,[/SUP][SUP]2[/SUP], Xia C[SUP]1,[/SUP][SUP]2[/SUP], Song YE[SUP]2[/SUP], Ngo H[SUP]1,[/SUP][SUP]2[/SUP], Studstill CJ[SUP]1,[/SUP][SUP]2[/SUP], Drews K[SUP]3[/SUP], Fox TE[SUP]4[/SUP], Johnson MC[SUP]2[/SUP], Hiscott J[SUP]5[/SUP], Kester M[SUP]4[/SUP], Alexander S[SUP]6[/SUP], Hahm B[SUP]7,[/SUP][SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 IFN-mediated innate immune responses against viral infection. Exogenous SPL expression inhibited influenza A virus replication, which correlated with an increase in type I IFN production and IFN-stimulated gene accumulation upon infection. In contrast, the lack of SPL expression led to an elevated cellular susceptibility to influenza A virus 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 the synthesis of type I IFNs. However, the S1P degradation-incompetent form of SPL also enhanced IFN responses, suggesting that SPL's pro-IFN function is independent of S1P. Biochemical analyses revealed that SPL, as well as the mutant form of SPL, interacts with IKKε. Importantly, when endogenous IKKε was downregulated using a small interfering RNA 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.
Copyright ? 2017 by The American Association of Immunologists, Inc.
PMID: 28600291 DOI: 10.4049/jimmunol.1601959