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Differential Reovirus-Specific and Herpesvirus-Specific Activator Protein 1 Activation of Secretogranin II Leads to Altered Virus Secretion

Significance Statement

There has been considerable work performed studying viruses and how they use hosts to replicate. However, much remains unknown about virus-host interactions and how they may be virus-specific.  In a previous quantitative study, we found reovirus strain T1L induced upregulation of the host secretogranin II (SCG2) protein, a protein not previously examined with respect to virus infections. The current study aimed to determine whether secretogranin II plays a role in infection. Herpes simplex type 1 virus also was studied because it is a ubiquitous virus that has co-evolved with humans over a very long time and is able to evade the host immune system and establish latent infections. We found that reovirus-induced secretogranin II upregulation, and phosphorylation, began at 18 hours post infection. Conversely, HSV-1 infection led to secretogranin II down regulation as early as 6 hours post infection. There was a negative correlation in the amount of secretogranin II and release of infectious virus from the cell. Analyses of the host AP-1 transcription pathway, known to activate secretogranin II expression, revealed a virus-specific difference in the secretogranin II activation pathway. This work aids in furthering our knowledge of virus-host interactions.

About The Author

Dr. Alicia Berard obtained her B.Sc. honours degree in Biochemistry from the University of Winnipeg, Canada in 2006. She began her graduate studies at the University of Manitoba, Canada under both Dr. Alberto Severini and Dr. Kevin Coombs supervisions. She recently received her PhD, in 2015, in Medical Microbiology where her work focused on host proteomics in reovirus and herpes simplex virus infections. She was supported during her degree with fellowship awards including the Manitoba Graduate Scholarship and Manitoba Health Research Council Health Sciences Centre Studentship awards. She is currently a postdoctoral fellow at the JC Wilt Infectious Diseases Research Centre, Canada, working on host proteomics in SIV/HIV infection in Dr. Adam Burgener’s laboratory.

About The Author

Dr. Kevin Coombs received his B.A.s in Biology and English from the State University of New York in Geneseo, N.Y., and his M.A. and Ph.D degrees from the University of Texas in Austin, TX. His post-doctoral training in molecular and structural virology was done in the labs of Dr. Bernard Fields at Harvard Medical School and Dr. Steven Harrison at Harvard University. Dr. Coombs is presently a Professor in the Department of Medical Microbiology and is Assistant Dean of Research for the College of Medicine in the Faculty of Health Sciences. He serves on several Editorial Boards of journals publishing in Cell Biology, Molecular Biology and Virology, has served as a panel member on NIH and AHFMR Peer Review Committees and as Scientific Officer and panel member on the CIHR Virology and Viral Pathogenesis Committee. His research interests include delineation of the protein and nucleic acid interactions in nucleoprotein complexes, using a variety of RNA viruses as models. This work is in general areas of:

* Generation and molecular characterization of assembly-defective virus mutants

* Inhibition of virus replication using pharmacologic inhibitors

* Mass spectrometry- and Systems-based analyses of virus and host protein alterations

* Development of non-pathogenic viruses as “bio-indicators” for wastewater and medical instrument disinfection.

Differential Reovirus-Specific and Herpesvirus-Specific Activator Protein 1 Activation of Secretogranin II Leads to Altered Virus Secretion. Global medical discovery

 

 

Journal Reference

J Virol. 2015 Dec;89(23):11954-64.

Berard AR1, Severini A2, Coombs KM3.

Show Affiliations
  1. 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.
  2. Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada.
  3. 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 [email protected]

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 secretogranin II upregulation and found secretogranin II phosphorylation by 18 h postinfection (hpi) in reovirus-infected cells. We also found a decrease in the amount of reovirus secretion from secretogranin II 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 protein1 (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 secretogranin II during infection.

IMPORTANCE:

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.

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