miR‐545 promoted enterovirus 71 replication via directly targeting phosphatase and tensin homolog and tumor necrosis factor receptor‐associated factor 6

Abstract

Enterovirus 71 (EV71) is a small, nonenveloped icosahedral RNA virus and is the predominant causative pathogen of hand‐foot‐and‐mouth disease. Recently, microRNAs (miRNAs) are reported to play important roles in the pathogenesis of EV71 replication. This study investigated the role of miR‐545 in the EV71 replication and explored the underlying molecular mechanisms. We showed that miR‐545 was upregulated in the EV71‐infected human embryonic kidney (HEK) 293 cells and rhabdomyosarcoma (RD) cells. Overexpression of miR‐545 promoted the viral replication of EV71 and attenuated the inhibitory effects of EV71 on cell viability in HEK293 and RD cells; while knockdown of miR‐545 significantly suppressed the EV71 replication in these two cell lines. Bioinformatics analysis and luciferase reporter assay showed that miR‐545 directly targeted the 3′untranslated region of phosphatase and tensin homolog (PTEN) and tumor necrosis factor receptor‐associated factor 6 (TRAF6) in HEK293 cells. Furthermore, miR‐545 negatively regulated the messenger RNA (mRNA) and protein expression of PTEN and TRAF6. The mRNA and protein expression of PTEN and TRAF6 was also suppressed by EV71 infection, which was attenuated by miR‐545 knockdown in HEK293 cells. Overexpression of PTEN and TRAF6 both suppressed the EV71 replication in HKE293 cells, and also attenuated the enhanced effects of miR‐545 overexpression on the EV71 replication in HEK293 cells. Collectively, our study for the first time showed that miR‐545 had an enhanced effect on the EV71 replication in HEK293 and RD cells. Further mechanistic results indicated that miR‐545 promoted EV71 replication at least partly via targeting PTEN and TRAF6.

MiR-4334-5p Facilitates Foot and Mouth Disease Virus Propagation by Suppressing Interferon Pathways via Direct Targeting ID1

“…Emerging evidences indicate that the host microRNAs (miRNAs) have a significant effect on the comprehensive host-pathogen interaction [ 7 ], even participating in the viral life cycle. For instance, miR-101 represses feline herpesvirus 1 reproduction by targeting cellular suppressor of cytokine signaling 5 to promote IFN-I signaling [ 20 ]; miR-7 suppresses rotavirus replication via targeting viral NSP5 directly [ 21 ]; miR-122 reduces HBV gene expression and replication via binding with hepatitis B virus pre-genomic RNA sequence [ 22 ]; miR-21-3p promotes influenza A virus H5N1 replication by regulating FGF2 to repress IFN-I signaling [ 23 ]; miR-545 promotes enterovirus 71 propagation through directly targeting phosphatase and tensin homolog and tumor necrosis factor receptor-associated factor 6 [ 24 ]. In the case of FMDV, there are only a few studies, artificial miRNA targeting 3D polymerase is efficient to inhibit FMDV replication [ 25 ], miR-1307 and miR-203a repress FMDV infection [ 2 , 15 ].…”

Downregulation of miR-155-5p facilitates enterovirus 71 replication through suppression of type I IFN response by targeting FOXO3/IRF7 pathway

“…In EV71 infection, miRNAs may be a double-edged sword. For example, Sun et al found that EV71 infection increased the level of miR-545 in HEK 293 cells, and EV71 replication was promoted by overexpression of miR-545 [43]. Another study performed by Zhao et al reported that miR-494-3p promoted EV71 replication by directly targeting PTEN [2].…”

Essential Role of Non-Coding RNAs in Enterovirus Infection: From Basic Mechanisms to Clinical Prospects

“…In addition, the protein-coding gene of eukaryotic translation initiation factor 4E (eIF4E) could be repressed by EVA71-induced miR-141, leading to continuous virus replication [54]. Upregulated miR-545 promoted EVA71 replication at least partly via targeting phosphatase and tensin homolog (PTEN) and tumor necrosis factor receptor-associated factor (TRAF)6 [55]. Several miRNAs such as miR-526a [56], miRNA-548 [57], miR-146a [58], and miR-21 [59] indirectly affected EV replication by influencing host innate immunity through various independent mechanisms.…”

“…Upregulated miR-628-5p upon EVA71 infection could target the 3'UTR of TRAF3, which further suppressed TRAF3-mediated IFN-β transcription in rhabdomyosarcoma cells(RD) [99]. EVA71 induced miR-545 in 293T cells and RD cells, which directly targeted the 3'UTR of TRAF6, leading to persistent viral replication [55]. It has also been reported that the expression of miR-146a, which targets interleukin-1 receptor-associated kinase 1 (IRAK 1) and TRAF6 involved in TLR signaling and type I IFN production, was significantly upregulated in EVA71-infected cells [58].…”