title: Meta- and Orthogonal Integration of Influenza "OMICs" Data Defines a Role for UBR4 in Virus Budding.
abstract: Several systems-level datasets designed to dissect host-pathogen interactions during influenza A infection have been reported. However, apparent discordance among these data has hampered their full utility toward advancing mechanistic and therapeutic knowledge. To collectively reconcile these datasets, we performed a meta-analysis of data from eight published RNAi screens and integrated these data with three protein interaction datasets, including one generated within the context of this study. Further integration of these data with global virus-host interaction analyses revealed a functionally validated biochemical landscape of the influenza-host interface, which can be queried through a simplified and customizable web portal (http://www.metascape.org/IAV). Follow-up studies revealed that the putative ubiquitin ligase UBR4 associates with the viral M2 protein and promotes apical transport of viral proteins. Taken together, the integrative analysis of influenza OMICs datasets illuminates a viral-host network of high-confidence human proteins that are essential for influenza A virus replication.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Shashank
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Marie O
authors.initials: MO
authors.lastname: Pohl
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Yingyao
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Rodriguez-Frandsen
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Stein
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Hong M
authors.initials: HM
authors.lastname: Moulton
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: DeJesus
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Che
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Lubbertus C F
authors.initials: LC
authors.lastname: Mulder
authors.affiliation: Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Emilio
authors.initials: E
authors.lastname: Yángüez
authors.affiliation: Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Dario
authors.initials: D
authors.lastname: Andenmatten
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Pache
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Balaji
authors.initials: B
authors.lastname: Manicassamy
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Randy A
authors.initials: RA
authors.lastname: Albrecht
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Gonzalez
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Quy
authors.initials: Q
authors.lastname: Nguyen
authors.affiliation: Microbiology and Physiological Systems (MaPS) Department, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Abraham
authors.initials: A
authors.lastname: Brass
authors.affiliation: Department of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02127, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Elledge
authors.affiliation: University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: White
authors.affiliation: Columbia University, Department of Systems Biology and Department of Microbiology and Immunology, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Sagi
authors.initials: S
authors.lastname: Shapira
authors.affiliation: Massachusetts General Hospital, 49 13th Street, Charlestown, MA 02129, USA.
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.affiliation: Max Planck Institute for Infection Biology, Charitéplatz 1, Campus Charité Mitte, 10117 Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Karlas
authors.affiliation: Max Planck Institute for Infection Biology, Charitéplatz 1, Campus Charité Mitte, 10117 Berlin, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Meyer
authors.affiliation: University of California, San Francisco, 1700 4th Street, Byers Hall 309, San Francisco, CA 94158, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Shales
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Gatorano
authors.affiliation: University of California, San Francisco, 1700 4th Street, Byers Hall 309, San Francisco, CA 94158, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Johnson
authors.affiliation: University of California, San Francisco, 1700 4th Street, Byers Hall 309, San Francisco, CA 94158, USA.
authors.forename: Gwen
authors.initials: G
authors.lastname: Jang
authors.affiliation: University of California, San Francisco, 1700 4th Street, Byers Hall 309, San Francisco, CA 94158, USA.
authors.forename: Tasha
authors.initials: T
authors.lastname: Johnson
authors.affiliation: University of California, San Francisco, 1700 4th Street, Byers Hall 309, San Francisco, CA 94158, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Verschueren
authors.affiliation: University of California, San Francisco, 1700 4th Street, Byers Hall 309, San Francisco, CA 94158, USA.
authors.forename: Doug
authors.initials: D
authors.lastname: Sanders
authors.affiliation: University of California, San Francisco, 1700 4th Street, Byers Hall 309, San Francisco, CA 94158, USA.
authors.forename: Nevan
authors.initials: N
authors.lastname: Krogan
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Shaw
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Host-Pathogen Interactions, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany; German Center for Infection Research (DZIF), 63225 Langen, Germany. Electronic address: renate.koenig@pei.de.
authors.forename: Renate
authors.initials: R
authors.lastname: König
authors.affiliation: Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address: stertz.silke@virology.uzh.ch.
authors.forename: Silke
authors.initials: S
authors.lastname: Stertz
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: adolfo.garcia-sastre@mssm.edu.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: schanda@sbpdiscovery.org.
authors.forename: Sumit K
authors.initials: SK
authors.lastname: Chanda
mesh_terms: D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D019295:Computational Biology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions; D006801:Humans; D047468:Immunoprecipitation; D009980:Influenza A virus / Q000502:physiology*; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D011485:Protein Binding; D060066:Protein Interaction Maps; D021381:Protein Transport; D044767:Ubiquitin-Protein Ligases; D014763:Viral Matrix Proteins / Q000378:metabolism*; D057074:Virus Release; D000086082:Viroporin Proteins
chemical_list: D002148:Calmodulin-Binding Proteins; D003598:Cytoskeletal Proteins; D044767:Ubiquitin-Protein Ligases; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins; C505833:UBR4 protein, human