MiR-199a Inhibits Secondary Envelopment of Herpes Simplex Virus-1 Through the Downregulation of Cdc42-specific GTPase Activating Protein Localized in Golgi Apparatus

• Published in: Scientific reports 2017-07, Vol.7 (1), p.6650-15, Article 6650
• Main Authors: Kobayashi, Kyousuke, Suemasa, Fumiko, Sagara, Hiroshi, Nakamura, Shinya, Ino, Yasushi, Kobayashi, Kazuyoshi, Hiramatsu, Hiroaki, Haraguchi, Takeshi, Kurokawa, Kazuo, Todo, Tomoki, Nakano, Akihiko, Iba, Hideo
• Format: Article
• Language: English
• Subjects: 13/109; 13/89; 14; 14/19; 14/28; 38; 38/70; 45/44; 631/326/596/1553; 631/337/384/331; 631/80/642/1525; cdc42 GTP-Binding Protein - genetics; Cdc42 protein; Cell Line, Tumor; Down-Regulation; Epithelial Cells - metabolism; Epithelial Cells - virology; Gene Expression Regulation; Golgi Apparatus - metabolism; Golgi cells; GTPase-activating protein; GTPase-Activating Proteins - metabolism; Guanosine triphosphatases; Herpes simplex; Herpes Simplex - genetics; Herpes Simplex - metabolism; Herpes viruses; Herpesvirus 1, Human - physiology; Humanities and Social Sciences; Humans; MicroRNAs - metabolism; multidisciplinary; Science; Science (multidisciplinary); Signal Transduction; Tumor cell lines; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-06754-3

Because several studies have shown that exogenous miR-199a has antiviral effects against various viruses, including herpesviruses, we examined how miR-199a exerts its antiviral effects using epithelial tumour cell lines infected with herpes simplex virus-1 (HSV-1). We found that both miR-199a-5p and -3p impair the secondary envelopment of HSV-1 by suppressing their common target, ARHGAP21, a Golgi-localized GTPase-activating protein for Cdc42. We further found that the trans -cisternae of the Golgi apparatus are a potential membrane compartment for secondary envelopment. Exogenous expression of either pre-miR-199a or sh-ARHGAP21 exhibited shared phenotypes i.e. alteration of Golgi function in uninfected cells, inhibition of HSV-1 secondary envelopment, and reduction of trans -Golgi proteins upon HSV-1 infection. A constitutively active form of Cdc42 also inhibited HSV-1 secondary envelopment. Endogenous levels of miR-199a in epithelial tumour cell lines were negatively correlated with the efficiency of HSV-1 secondary envelopment within these cells. These results suggest that miR-199a is a crucial regulator of Cdc42 activity on Golgi membranes, which is important for the maintenance of Golgi function and for the secondary envelopment of HSV-1 upon its infection.