title: A role for endoplasmic reticulum exit sites in foot-and-mouth disease virus infection.
abstract: Picornaviruses replicate their genomes in association with cellular membranes. While enteroviruses are believed to utilize membranes of the early secretory pathway, the origin of the membranes used by foot-and-mouth disease virus (FMDV) for replication are unknown. Secretory-vesicle traffic through the early secretory pathway is mediated by the sequential acquisition of two distinct membrane coat complexes, COPII and COPI, and requires the coordinated actions of Sar1, Arf1 and Rab proteins. Sar1 is essential for generating COPII vesicles at endoplasmic reticulum (ER) exit sites (ERESs), while Arf1 and Rab1 are required for subsequent vesicle transport by COPI vesicles. In the present study, we have provided evidence that FMDV requires pre-Golgi membranes of the early secretory pathway for infection. Small interfering RNA depletion of Sar1 or expression of a dominant-negative (DN) mutant of Sar1a inhibited FMDV infection. In contrast, a dominant-active mutant of Sar1a, which allowed COPII vesicle formation but inhibited the secretory pathway by stabilizing COPII coats, caused major disruption to the ER-Golgi intermediate compartment (ERGIC) but did not inhibit infection. Treatment of cells with brefeldin A, or expression of DN mutants of Arf1 and Rab1a, disrupted the Golgi and enhanced FMDV infection. These results show that reagents that block the early secretory pathway at ERESs have an inhibitory effect on FMDV infection, while reagents that block the early secretory pathway immediately after ER exit but before the ERGIC and Golgi make infection more favourable. Together, these observations argue for a role for Sar1 in FMDV infection and that initial virus replication takes place on membranes that are formed at ERESs.
authors: The Pirbright Institute, Pirbright, Surrey GU24 0NF, UK.
authors: Rebecca
authors: R
authors: Midgley
authors: The Pirbright Institute, Pirbright, Surrey GU24 0NF, UK.
authors: Katy
authors: K
authors: Moffat
authors: The Pirbright Institute, Pirbright, Surrey GU24 0NF, UK.
authors: Stephen
authors: S
authors: Berryman
authors: The Pirbright Institute, Pirbright, Surrey GU24 0NF, UK.
authors: Philippa
authors: P
authors: Hawes
authors: The Pirbright Institute, Pirbright, Surrey GU24 0NF, UK.
authors: Jennifer
authors: J
authors: Simpson
authors: The Pirbright Institute, Pirbright, Surrey GU24 0NF, UK.
authors: Daniel
authors: D
authors: Fullen
authors: Cell Biology Laboratories, School of Biochemistry, Medical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors: David J
authors: DJ
authors: Stephens
authors: The Pirbright Institute, Pirbright, Surrey GU24 0NF, UK.
authors: Alison
authors: A
authors: Burman
authors: The Pirbright Institute, Pirbright, Surrey GU24 0NF, UK.
authors: Terry
authors: T
authors: Jackson
mesh_terms: D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure* / Q000821:virology*; D029544:Foot-and-Mouth Disease Virus / Q000472:pathogenicity* / Q000502:physiology; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D021381:Protein Transport; D055571:Secretory Pathway; D013552:Swine; D014779:Virus Replication
chemical_list: C493083:SAR1A protein, human; D020559:Monomeric GTP-Binding Proteins
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