Abstract
BackgroundEnterovirus 71 (EV71) usually infects infants causing hand-foot-mouth disease (HFMD), even fatal neurological disease like aseptic meningitis. Effective drug for preventing and treating EV71 infection is unavailable currently. EV71 3C mediated the cleavage of many proteins and played an important role in viral inhibiting host innate immunity. Promyelocytic leukemia (PML) protein, the primary organizer of PML nuclear bodies (PML-NBs), can be induced by interferon and is involved in antiviral activity. PML inhibits EV71 replication, and EV71 infection reduces PML expression, but the molecular mechanism is unclear.MethodsThe cleavage of PMLIII and IV was confirmed by co-transfection of EV71 3C protease and PML. The detailed cleavage sites were evaluated further by constructing the Q to A mutant of PML. PML knockout cells were infected with EV71 to identify the effect of cleavage on EV71 replication. Immunofluorescence analysis to examine the interference of EV71 3C on the formation of PML-NBs.ResultsEV71 3C directly cleaved PMLIII and IV. Furthermore, 3C cleaved PMLIV at the sites of Q430–A431 and Q444–S445 through its protease activity. Overexpression of PMLIV Q430A/Q444A variant exhibited stronger antiviral potential than the wild type. PMLIV Q430A/Q444A formed normal nuclear bodies that were not affected by 3C, suggesting that 3C may impair PML-NBs production via PMLIV cleavage and counter its antiviral activities. PML, especially PMLIV, which sequesters viral proteins in PML-NBs and inhibits viral production, is a novel target of EV71 3C cleavage.ConclusionsEV71 3C cleaves PMLIV at Q430–A431 and Q444–S445. Cleavage reduces the antiviral function of PML and decomposes the formation of PML-NBs, which is conducive to virus replication.
Highlights
Enterovirus 71 (EV71) usually infects infants causing hand-foot-mouth disease (HFMD), even fatal neurological disease like aseptic meningitis
This study demonstrated that Promyelocytic leukemia (PML) could be cleaved by EV71 3C protease independent of its RNA binding activity and identified the cleavage sites of PMLIV, the isoform that could suppress EV71 replication
Considered that EV71 3C protein was mainly functioned as a protease to cleave virus precursor protein and multiple host proteins, we hypothesized that EV71 3C might cleave nuclear PML isoforms which are major organizers of PML nuclear bodies (PML-nuclear bodies (NBs))
Summary
Enterovirus 71 (EV71) usually infects infants causing hand-foot-mouth disease (HFMD), even fatal neurological disease like aseptic meningitis. EV71 3C mediated the cleavage of many proteins and played an important role in viral inhibiting host innate immunity. EV71 is a non-enveloped virus with a single-stranded, positive-sensed RNA genome of approximately 7.5 kb [10, 11]. It contains one open reading frame (ORF) and encodes a single polyprotein precursor, which is subsequently split into four structural (VP1, VP2, VP3, and VP4) and seven nonstructural (2A, 2B, 2C, 3A, 3B, 3C, and 3D) proteins [12]. Considering its important role in virus life, targeting 3C protein has become a potential way to combat EV71 infection
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