title: Sphingosine kinase 1 serves as a pro-viral factor by regulating viral RNA synthesis and nuclear export of viral ribonucleoprotein complex upon influenza virus infection.
abstract: Influenza continues to pose a threat to humans by causing significant morbidity and mortality. Thus, it is imperative to investigate mechanisms by which influenza virus manipulates the function of host factors and cellular signal pathways. In this study, we demonstrate that influenza virus increases the expression and activation of sphingosine kinase (SK) 1, which in turn regulates diverse cellular signaling pathways. Inhibition of SK suppressed virus-induced NF-κB activation and markedly reduced the synthesis of viral RNAs and proteins. Further, SK blockade interfered with activation of Ran-binding protein 3 (RanBP3), a cofactor of chromosome region maintenance 1 (CRM1), to inhibit CRM1-mediated nuclear export of the influenza viral ribonucleoprotein complex. In support of this observation, SK inhibition altered the phosphorylation of ERK, p90RSK, and AKT, which is the upstream signal of RanBP3/CRM1 activation. Collectively, these results indicate that SK is a key pro-viral factor regulating multiple cellular signal pathways triggered by influenza virus infection.
authors.affiliation: Departments of Surgery & Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, Missouri, United States of America.
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Seo
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Pritzl
authors.forename: Madhuvanthi
authors.initials: M
authors.lastname: Vijayan
authors.forename: Kavita
authors.initials: K
authors.lastname: Bomb
authors.forename: Mariah E
authors.initials: ME
authors.lastname: McClain
authors.forename: Stephen
authors.initials: S
authors.lastname: Alexander
authors.forename: Bumsuk
authors.initials: B
authors.lastname: Hahm
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061985:Madin Darby Canine Kidney Cells; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012367:RNA, Viral / Q000096:biosynthesis*; D012261:Ribonucleoproteins / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D000099157:Sphingosine Kinase
chemical_list: D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D012367:RNA, Viral; D012261:Ribonucleoproteins; D014764:Viral Proteins; D000099157:Sphingosine Kinase; C112820:RANBP3 protein, human