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

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

Vaccine and Gene Therapy Institute

Research output: Contribution to journal › Article › peer-review

127 Scopus citations

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.

Original language	English (US)
Pages (from-to)	363-373
Number of pages	11
Journal	Cell Host and Microbe
Volume	15
Issue number	3
DOIs	https://doi.org/10.1016/j.chom.2014.02.004
State	Published - Mar 12 2014

Funding

We wish to thank Drs. Richard Goodman, Louis Picker, Klaus Frueh, and Patrizia Caposio for their helpful comments on this paper, and Andrew Townsend for help with graphics. We thank Renee Espinoza-Najera, Chantel Pelton, and Helen Hewitt for technical assistance. This research was supported by grants AI21640 (J.A.N.), AI50189 (W.B.), and AI035602 (W.B.) from the National Institutes of Health.

Funders	Funder number
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health
National Institute of Allergy and Infectious Diseases	R01AI050189

ASJC Scopus subject areas

Parasitology
Microbiology
Virology

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10.1016/j.chom.2014.02.004

Cite this

Hook, L. M., Grey, F., Grabski, R., Tirabassi, R., Doyle, T., Hancock, M., Landais, I., Jeng, S., McWeeney, S., Britt, W., & Nelson, J. A. (2014). Cytomegalovirus miRNAs target secretory pathway genes to facilitate formation of the virion assembly compartment and reduce cytokine secretion. Cell Host and Microbe, 15(3), 363-373. https://doi.org/10.1016/j.chom.2014.02.004

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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.",

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AU - Britt, William

AU - Nelson, Jay A.

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

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