TY - JOUR
T1 - Cytomegalovirus miRNAs target secretory pathway genes to facilitate formation of the virion assembly compartment and reduce cytokine secretion
AU - Hook, Lauren M.
AU - Grey, Finn
AU - Grabski, Robert
AU - Tirabassi, Rebecca
AU - Doyle, Tracy
AU - Hancock, Meaghan
AU - Landais, Igor
AU - Jeng, Sophia
AU - McWeeney, Shannon
AU - Britt, William
AU - Nelson, Jay A.
N1 - Funding Information:
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.
PY - 2014/3/12
Y1 - 2014/3/12
N2 - 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.
AB - 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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U2 - 10.1016/j.chom.2014.02.004
DO - 10.1016/j.chom.2014.02.004
M3 - Article
C2 - 24629342
AN - SCOPUS:84896090853
SN - 1931-3128
VL - 15
SP - 363
EP - 373
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 3
ER -