Cytomegalovirus miRNAs target secretory pathway genes to facilitate formation of the virion assembly compartment and reduce cytokine secretion

Lauren M Hook; Finn Grey; Robert Grabski; Rebecca Tirabassi; Tracy Doyle; Meaghan Hancock; Igor Landais; Sophia Jeng; Shannon McWeeney; William Britt; Jay A Nelson

doi:10.1016/j.chom.2014.02.004

Cytomegalovirus miRNAs target secretory pathway genes to facilitate formation of the virion assembly compartment and reduce cytokine secretion

Cell Host Microbe. 2014 Mar 12;15(3):363-73. doi: 10.1016/j.chom.2014.02.004.

Authors

Affiliations

¹ Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA.
² 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.
³ Department of Pediatrics, University of Alabama, Birmingham, AL 35294, USA.
⁴ 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.
⁵ Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁶ Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
⁷ Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA. Electronic address: nelsonj@ohsu.edu.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Cytokines / antagonists & inhibitors*
Cytokines / metabolism
Cytomegalovirus / genetics
Cytomegalovirus / physiology*
Golgi Apparatus / physiology
Golgi Apparatus / virology
Host-Pathogen Interactions*
Humans
MicroRNAs / genetics*
MicroRNAs / metabolism*
Secretory Pathway / genetics*
Virus Assembly*

Substances

Cytokines
MicroRNAs

Abstract

Publication types

MeSH terms

Substances

Grants and funding