title: Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection.
abstract: Viruses are obligate parasites and thus require the machinery of the host cell to replicate. Inhibition of host factors co-opted during active infection is a strategy hosts use to suppress viral replication and a potential pan-antiviral therapy. To define the cellular proteins and processes required for a virus during infection is thus crucial to understanding the mechanisms of virally induced disease. In this report, we generated fully infectious tagged influenza viruses and used infection-based proteomics to identify pivotal arms of cellular signaling required for influenza virus growth and infectivity. Using mathematical modeling and genetic and pharmacologic approaches, we revealed that modulation of Sec61-mediated cotranslational translocation selectively impaired glycoprotein proteostasis of influenza as well as HIV and dengue viruses and led to inhibition of viral growth and infectivity. Thus, by studying virus-human protein-protein interactions in the context of active replication, we have identified targetable host factors for broad-spectrum antiviral therapies.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Heaton
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Moshkina
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Romain
authors.initials: R
authors.lastname: Fenouil
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gardner
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Aguirre
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: Priya S
authors.initials: PS
authors.lastname: Shah
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Manganaro
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: Judd F
authors.initials: JF
authors.lastname: Hultquist
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Justine
authors.initials: J
authors.lastname: Noel
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sachs
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hamilton
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Leon
authors.affiliation: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Division of Hematology and Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Chawdury
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Shashank
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Camilla
authors.initials: C
authors.lastname: Melegari
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Campisi
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Hai
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Giorgi
authors.initials: G
authors.lastname: Metreveli
authors.affiliation: Fundación Instituto Leloir-CONICET, Avenida Patricias Argentinas 435, Buenos Aires 1405, Argentina.
authors.forename: Andrea V
authors.initials: AV
authors.lastname: Gamarnik
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.affiliation: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Division of Hematology and Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Greenbaum
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Viviana
authors.initials: V
authors.lastname: Simon
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Sesma
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: Nevan J
authors.initials: NJ
authors.lastname: Krogan
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Lubbertus C F
authors.initials: LCF
authors.lastname: Mulder
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Harm
authors.initials: H
authors.lastname: van Bakel
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Tortorella
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Palese
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA. Electronic address: ivan.marazzi@mssm.edu.
authors.forename: Ivan
authors.initials: I
authors.lastname: Marazzi
mesh_terms: D003716:Dengue Virus / Q000472:pathogenicity / Q000502:physiology; D006678:HIV / Q000472:pathogenicity / Q000502:physiology; D006790:Host-Parasite Interactions / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D009980:Influenza A virus / Q000472:pathogenicity* / Q000502:physiology*; D013058:Mass Spectrometry; D008962:Models, Theoretical; D017510:Protein Folding; D040901:Proteomics; D014779:Virus Replication / Q000502:physiology*