title: Morbillivirus glycoprotein expression induces ER stress, alters Ca2+ homeostasis and results in the release of vasostatin.
abstract: Although the pathology of Morbillivirus in the central nervous system (CNS) is well described, the molecular basis of neurodegenerative events still remains poorly understood. As a model to explore Morbillivirus-mediated CNS dysfunctions, we used canine distemper virus (CDV) that we inoculated into two different cell systems: a monkey cell line (Vero) and rat primary hippocampal neurons. Importantly, the recombinant CDV used in these studies not only efficiently infects both cell types but recapitulates the uncommon, non-cytolytic cell-to-cell spread mediated by virulent CDVs in brain of dogs. Here, we demonstrated that both CDV surface glycoproteins (F and H) markedly accumulated in the endoplasmic reticulum (ER). This accumulation triggered an ER stress, characterized by increased expression of the ER resident chaperon calnexin and the proapoptotic transcription factor CHOP/GADD 153. The expression of calreticulin (CRT), another ER resident chaperon critically involved in the response to misfolded proteins and in Ca(2+) homeostasis, was also upregulated. Transient expression of recombinant CDV F and H surface glycoproteins in Vero cells and primary hippocampal neurons further confirmed a correlation between their accumulation in the ER, CRT upregulation, ER stress and disruption of ER Ca(2+) homeostasis. Furthermore, CDV infection induced CRT fragmentation with re-localisation of a CRT amino-terminal fragment, also known as vasostatin, on the surface of infected and neighbouring non-infected cells. Altogether, these results suggest that ER stress, CRT fragmentation and re-localization on the cell surface may contribute to cytotoxic effects and ensuing cell dysfunctions triggered by Morbillivirus, a mechanism that might potentially be relevant for other neurotropic viruses.
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Brunner
authors.forename: Philippe
authors.initials: P
authors.lastname: Plattet
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Doucey
authors.forename: Lia
authors.initials: L
authors.lastname: Rosso
authors.forename: Thomas
authors.initials: T
authors.lastname: Curie
authors.forename: Alexandra
authors.initials: A
authors.lastname: Montagner
authors.forename: Riccardo
authors.initials: R
authors.lastname: Wittek
authors.forename: Marc
authors.initials: M
authors.lastname: Vandelvelde
authors.forename: Andreas
authors.initials: A
authors.lastname: Zurbriggen
authors.forename: Harald
authors.initials: H
authors.lastname: Hirling
authors.forename: Béatrice
authors.initials: B
authors.lastname: Desvergne
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D037282:Calreticulin / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D004217:Distemper Virus, Canine / Q000235:genetics* / Q000502:physiology; D059865:Endoplasmic Reticulum Stress; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology; D006706:Homeostasis; D009474:Neurons / Q000378:metabolism / Q000821:virology; D010446:Peptide Fragments / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D015854:Up-Regulation; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D037282:Calreticulin; D006023:Glycoproteins; D010446:Peptide Fragments; D014764:Viral Proteins; C121986:vasostatin; D002118:Calcium