Enterovirus 71 VP1 promotes 5-HT release by upregulating the expression of ERICH3 and methyltransferase ZC3H13

Abstract

Background and aim: The effect of structural viral protein 1 (VP1) on neurological damage caused by enterovirus 71 (EV71) infection is unclear. This study aimed to explore the transcriptome changes in EV infected patients and the role of VP1 on the cell secretion pathway of neuron cells. Methods: In our cohort, EV infected patients were enrolled, and RNA-seq analysis was used to evaluate the distinct transcript patterns of cerebrospinal fluid (CSF). The EV71 VP1-overexpressing vector (pEGFP-c3-VP1) was generated and transfected into neuron cells. The relationship between Glutamate Rich 3 (ERICH3) and methyltransferase Zinc Finger CCCH-Type Containing 13 (ZC3H13) and their effect on the serotonin (5-HT) release of neuron cells were explored using small interfering RNA. The expression of ERICH3 and ZC3H13 and concentration of 5-HT were determined using real-time PCR, Western blot, and ELISA, respectively. Result: The expression of ERICH3 and ZC3H13 were significantly upregulated in EV infected patients with neurological symptoms compared to those without (P < 0.05). The ERICH3 gene had many N6-methyladenosine (m6A) binding sites that can be regulated by m6A modification. Further, the expression of ERICH3 and ZC3H13 were elevated significantly in EV71-VP1 overexpressing neuron cells (P < 0.05). Moreover, ERICH3 or ZC3H13 deficiency could significantly downregulate the release of 5-HT in VP1-overexpressing cells (P < 0.05). Nonetheless, ERICH3 expression was significantly suppressed when ZC3H13 was silenced in neuron cells and vice versa (P < 0.05). Conclusions: EV71-VP1 can promote 5-HT release by upregulating the expression of ERICH3 and ZC3H13. 5-HT might be a novel therapeutic target for EV71 infection-induced fatal neuronal damage.

Keywords

• Enterovirus 71 structural viral protein 1
• m6A methylation
• Serotonin
• Glutamate-rich 3