title: Differential Reovirus-Specific and Herpesvirus-Specific Activator Protein 1 Activation of Secretogranin II Leads to Altered Virus Secretion.
abstract: Viruses utilize host cell machinery for propagation and manage to evade cellular host defense mechanisms in the process. Much remains unknown regarding how the host responds to viral infection. We recently performed global proteomic screens of mammalian reovirus TIL- and T3D-infected and herpesvirus (herpes simplex virus 1 [HSV-1])-infected HEK293 cells. The nonenveloped RNA reoviruses caused an upregulation, whereas the enveloped DNA HSV-1 caused a downregulation, of cellular secretogranin II (SCG2). SCG2, a member of the granin family that functions in hormonal peptide sorting into secretory vesicles, has not been linked to virus infections previously. We confirmed SCG2 upregulation and found SCG2 phosphorylation by 18 h postinfection (hpi) in reovirus-infected cells. We also found a decrease in the amount of reovirus secretion from SCG2 knockdown cells. Similar analyses of cells infected with HSV-1 showed an increase in the amount of secreted virus. Analysis of the stress-activated protein kinase (SAPK)/Jun N-terminal protein kinase (JNK) pathway indicated that each virus activates different pathways leading to activator protein 1 (AP-1) activation, which is the known SCG2 transcription activator. We conclude from these experiments that the negative correlation between SCG2 quantity and virus secretion for both viruses indicates a virus-specific role for SCG2 during infection.
  
  
  OBJECTIVE
  Mammalian reoviruses affect the gastrointestinal system or cause respiratory infections in humans. Recent work has shown that all mammalian reovirus strains (most specifically T3D) may be useful oncolytic agents. The ubiquitous herpes simplex viruses cause common sores in mucosal areas of their host and have coevolved with hosts over many years. Both of these virus species are prototypical representatives of their viral families, and investigation of these viruses can lead to further knowledge of how they and the other more pathogenic members of their respective families interact with the host. Here we show that secretogranin II (SCG2), a protein not previously studied in the context of virus infections, alters virus output in a virus-specific manner and that the quantity of SCG2 is inversely related to amounts of infectious-virus secretion. Herpesviruses may target this protein to facilitate enhanced virus release from the host.
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada Manitoba Center for Proteomics and Systems Biology, John Buhler Research Center, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Berard
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada.
authors.forename: Alberto
authors.initials: A
authors.lastname: Severini
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada Manitoba Center for Proteomics and Systems Biology, John Buhler Research Center, University of Manitoba, Winnipeg, MB, Canada Manitoba Institute of Child Health, University of Manitoba, Winnipeg, MB, Canada kevin.coombs@umanitoba.ca.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Coombs
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D018259:Herpesvirus 1, Human / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008856:Microscopy, Fluorescence; D030102:Orthoreovirus, Mammalian / Q000378:metabolism*; D010766:Phosphorylation; D053381:Secretogranin II / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014709:Vero Cells; D057074:Virus Release / Q000502:physiology*
chemical_list: D053381:Secretogranin II; D018808:Transcription Factor AP-1