title: Integrated systems biology analysis of KSHV latent infection reveals viral induction and reliance on peroxisome mediated lipid metabolism.
abstract: Kaposi's Sarcoma associated Herpesvirus (KSHV), an oncogenic, human gamma-herpesvirus, is the etiological agent of Kaposi's Sarcoma the most common tumor of AIDS patients world-wide. KSHV is predominantly latent in the main KS tumor cell, the spindle cell, a cell of endothelial origin. KSHV modulates numerous host cell-signaling pathways to activate endothelial cells including major metabolic pathways involved in lipid metabolism. To identify the underlying cellular mechanisms of KSHV alteration of host signaling and endothelial cell activation, we identified changes in the host proteome, phosphoproteome and transcriptome landscape following KSHV infection of endothelial cells. A Steiner forest algorithm was used to integrate the global data sets and, together with transcriptome based predicted transcription factor activity, cellular networks altered by latent KSHV were predicted. Several interesting pathways were identified, including peroxisome biogenesis. To validate the predictions, we showed that KSHV latent infection increases the number of peroxisomes per cell. Additionally, proteins involved in peroxisomal lipid metabolism of very long chain fatty acids, including ABCD3 and ACOX1, are required for the survival of latently infected cells. In summary, novel cellular pathways altered during herpesvirus latency that could not be predicted by a single systems biology platform, were identified by integrated proteomics and transcriptomics data analysis and when correlated with our metabolomics data revealed that peroxisome lipid metabolism is essential for KSHV latent infection of endothelial cells.
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, United States of America.|Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Zoi E
authors.initials: ZE
authors.lastname: Sychev
authors.affiliation: Department of Genome Science, University of Washington, Seattle, Washington, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: Hu
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Terri A
authors.identifier: 0000-0002-8670-2884
authors.initials: TA
authors.lastname: DiMaio
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison and Morgridge Institute for Research, Madison, Wisconsin, USA.
authors.forename: Anthony
authors.identifier: 0000-0002-5324-9833
authors.initials: A
authors.lastname: Gitter
authors.affiliation: Department of Genome Science, University of Washington, Seattle, Washington, United States of America.
authors.forename: Nathan D
authors.identifier: 0000-0002-1216-5262
authors.initials: ND
authors.lastname: Camp
authors.affiliation: Department of Genome Science, University of Washington, Seattle, Washington, United States of America.
authors.forename: William S
authors.identifier: 0000-0001-7283-4715
authors.initials: WS
authors.lastname: Noble
authors.affiliation: Department of Genome Science, University of Washington, Seattle, Washington, United States of America.
authors.forename: Alejandro
authors.identifier: 0000-0003-2909-3880
authors.initials: A
authors.lastname: Wolf-Yadlin
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Lagunoff
mesh_terms: D002469:Cell Separation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000821:virology; D005434:Flow Cytometry; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006790:Host-Parasite Interactions / Q000502:physiology*; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D020675:Peroxisomes / Q000378:metabolism*; D034741:RNA, Small Interfering; D012514:Sarcoma, Kaposi / Q000821:virology; D049490:Systems Biology; D014162:Transfection; D014775:Virus Activation / Q000502:physiology*; D017735:Virus Latency / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering