Abstract
Nucleoside diphosphate kinase 1 (NME1) is well-known as a tumor suppressor that regulates p53 function to prevent cancer metastasis and progression. However, the role of NME1 in virus-infected cells remains unknown. Here, we showed that NME1 suppresses viral replication in foot-and-mouth disease virus (FMDV)-infected cells. NME1-enhanced p53-mediated transcriptional activity and induction of interferon-inducible antiviral genes expression. FMDV infection decreased NME1 protein expression. The 2B and VP4 proteins were identified as the viral factors that induced reduction of NME1. FMDV 2B protein has a suppressive effect on host protein expression. We measured, for the first time, VP4-induced lysosomal degradation of host protein; VP4-induced degradation of NME1 through the macroautophagy pathway, and impaired p53-mediated signaling. p53 plays significant roles in antiviral innate immunity by inducing several interferon-inducible antiviral genes expression, such as, ISG20, IRF9, RIG-I, and ISG15. VP4 promoted interaction of p53 with murine double minute 2 (MDM2) through downregulation of NME1 resulting in destabilization of p53. Therefore, 5-flurouracil-induced upregulation of ISG20, IRF9, RIG-I, and ISG15 were suppressed by VP4. VP4-induced reduction of NME1 was not related to the well-characterized blocking effect of FMDV on cellular translation, and no direct interaction was detected between NME1 and VP4. The 15–30 and 75–85 regions of VP4 were determined to be crucial for VP4-induced reduction of NME1. Deletion of these VP4 regions also inhibited the suppressive effect of VP4 on NME1-enhanced p53 signaling. In conclusion, these data suggest an antiviral role of NME1 by regulation of p53-mediated antiviral innate immunity in virus-infected cells, and reveal an antagonistic mechanism of FMDV that is mediated by VP4 to block host innate immune antiviral response.
Highlights
Foot-and-mouth disease (FMD) is a highly contagious disease that mainly affects pigs, cows, sheep, goats, deer, and other cloven-hoofed animals
foot-and-mouth disease virus (FMDV) infection suppresses NME1 protein expression To investigate the state of NME1 in FMDV-infected cells, PK-15 cells were mock-infected or infected with FMDV at different times; and NME1 transcript and protein levels were examined by quantitative polymerase chain reaction and Western blotting, respectively
FMDV infection had no effect on NME1 transcripts at 16 h post-infection, and no significant changes in NME1 mRNA levels were observed in mockinfected cells (Fig. 1a)
Summary
Foot-and-mouth disease (FMD) is a highly contagious disease that mainly affects pigs, cows, sheep, goats, deer, and other cloven-hoofed animals. The causative agent of FMD is the foot-and-mouth disease virus (FMDV), which. Nucleoside diphosphate kinase 1 (NME1, known as NM23-H1) has a metastasis-suppressive function in Official journal of the Cell Death Differentiation Association. It is suggested that NME1 has an effect on the cell-adhesion-related signaling pathway and plays critical roles in cellular proliferation, signal transduction, growth control, embryonic development, differentiation, and oncogenesis[4,5]. It is proposed that NME1 interacts with the macrophage migration inhibitory factor (MIF), which is a pluripotent cytokine involved in host immune and inflammatory responses and tumorigenesis[6]. This interaction between NME1 and MIF may result in a negative regulatory effect of NME1 on tumor metastasis
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