title: Cytomegalovirus miRNAs target secretory pathway genes to facilitate formation of the virion assembly compartment and reduce cytokine secretion.
abstract: Herpesviruses, including human cytomegalovirus (HCMV), encode multiple microRNAs (miRNA) whose targets are just being uncovered. Moreover, miRNA function during the virus life cycle is relatively unknown. We find that HCMV miRs UL112-1, US5-1, and US5-2 target multiple components of the host secretory pathway, including VAMP3, RAB5C, RAB11A, SNAP23, and CDC42. A HCMV miR UL112-1, US5-1, and US5-2 triple mutant displayed aberrant morphogenesis of the virion assembly compartment (VAC), increased secretion of noninfectious particles, and increased IL-6 release from infected cells. Ectopic expression of miRs UL112-1, US5-1, and US5-2 or siRNAs directed against RAB5C, RAB11A, SNAP23, and CDC42 caused the loss of Golgi stacks with reorganization into structures that resemble the VAC and a decrease in cytokine release. These observations indicate that multiple HCMV miRNAs coordinately regulate reorganization of the secretory pathway to control cytokine secretion and facilitate formation of the VAC for efficient infectious virus production.
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Hook
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA; Division of Infection and Immunity, The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.
authors.forename: Finn
authors.initials: F
authors.lastname: Grey
authors.affiliation: Department of Pediatrics, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Grabski
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA; Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Tirabassi
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Doyle
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA.
authors.forename: Meaghan
authors.initials: M
authors.lastname: Hancock
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Landais
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Jeng
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: McWeeney
authors.affiliation: Department of Pediatrics, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: William
authors.initials: W
authors.lastname: Britt
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA. Electronic address: nelsonj@ohsu.edu.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Nelson
mesh_terms: D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics / Q000502:physiology*; D006056:Golgi Apparatus / Q000502:physiology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D055571:Secretory Pathway / Q000235:genetics*; D019065:Virus Assembly
chemical_list: D016207:Cytokines; D035683:MicroRNAs