title: Human cytomegalovirus regulates bioactive sphingolipids.
abstract: Sphingolipids are present in membranes of all eukaryotic cells. Bioactive sphingolipids also function as signaling molecules that regulate cellular processes such as proliferation, migration, and apoptosis. Human cytomegalovirus (HCMV) exploits a variety of cellular signaling pathways to promote its own replication. However, whether HCMV modulates lipid signaling pathways is an essentially unexplored area of research in virus-host cell interactions. In this study, we examined the accumulation of the bioactive sphingolipids and the enzymes responsible for the biosynthesis and degradation of these lipids. HCMV infection results in increased accumulation and activity of sphingosine kinase (SphK), the enzyme that generates sphingosine 1-phosphate (S1P) and dihydrosphingosine 1-phosphate (dhS1P). We also utilized a mass spectrometry approach to generate a sphingolipidomic profile of HCMV-infected cells. We show that HCMV infection results in increased levels of dhS1P and ceramide at 24 h, suggesting an enhancement of de novo sphingolipid synthesis. Subsequently dihydrosphingosine and dhS1P decrease at 48 h consistent with attenuation of de novo sphingolipid synthesis. Finally, we present evidence that de novo sphingolipid synthesis and sphingosine kinase activity directly impact virus gene expression and virus growth. Together, these findings demonstrate that host cell sphingolipids are dynamically regulated upon infection with a herpes virus in a manner that impacts virus replication.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Machesky
authors.forename: Guojuan
authors.initials: G
authors.lastname: Zhang
authors.forename: Bindu
authors.initials: B
authors.lastname: Raghavan
authors.forename: Pete
authors.initials: P
authors.lastname: Zimmerman
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Kelly
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
authors.forename: W James
authors.initials: WJ
authors.lastname: Waldman
authors.forename: James R
authors.initials: JR
authors.lastname: Van Brocklyn
authors.forename: Joanne
authors.initials: J
authors.lastname: Trgovcich
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D017781:Genes, Immediate-Early; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods; D008954:Models, Biological; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D034622:RNA Interference; D013107:Sphingolipids / Q000737:chemistry*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013997:Time Factors; D014779:Virus Replication; D000099157:Sphingosine Kinase
chemical_list: D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013107:Sphingolipids; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060504:dihydrosphingosine 1-phosphate; C060506:sphingosine 1-phosphate