Recent Progress on Functional Genomics Research of Enterovirus 71
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Enterovirus 71 (EV71) is one of the main pathogens that causes hand-foot-and-mouth disease (HFMD). HFMD caused by EV71 infection is mostly self-limited; however, some infections can cause severe neurological diseases, such as aseptic meningitis, brain stem encephalitis, and even death. There are still no effective clinical drugs used for the prevention and treatment of HFMD. Studying EV71 protein function is essential for elucidating the EV71 replication process and developing anti-EV71 drugs and vaccines. In this review, we summarized the recent progress in the studies of EV71 non-coding regions (5′ UTR and 3′ UTR) and all structural and nonstructural proteins, especially the key motifs involving in viral infection, replication, and immune regulation. This review will promote our understanding of EV71 virus replication and pathogenesis, and will facilitate the development of novel drugs or vaccines to treat EV71.
KeywordsEnterovirus 71 (EV71) Functional genomics Structural protein Nonstructural protein Viral protein function
Enterovirus 71 (EV71), a single-stranded RNA virus with a genome length of approximately 7.5 kb, belongs to the genus Enterovirus within the family Picornaviridae (Wang et al.2012a, b). Since it was first discovered in 1969, EV71 has caused numerous outbreaks and epidemics worldwide, particularly in Asian and Pacific regions, such as China, Korea, Singapore, Japan, and Vietnam (WHO 2018). EV71 usually infects infants and young children under the age of 5 years, and hand-foot-and-mouth disease caused by EV71 infection is usually self-limited. However, some infections can cause aseptic meningitis, brain stem encephalitis, and other nervous system diseases (Weng et al.2010; Teoh et al.2016). At present, there are no effective drugs to prevent and treat EV71 infection, and ribavirin, interferon (IFN), and other drugs are used only for symptomatic treatment (Yi et al.2011; Wang et al.2017a). Studying the structure and function of the EV71 viral genome is essential for understanding the EV71 replication process and developing anti-EV71 drugs and vaccines.
In this review, we discuss the important functions of the EV71 genome, based on recent functional genomics research.
Structural Features and Replication Process of the EV71 Genome
As a nonenveloped virus, the host cell entry mechanism of EV71 remains largely unknown. Recent data have indicated that the interaction between viral particles and receptors causes the spatial configuration to change and results in loss of VP4; eventually, the virus particles enter the cell through the endocytotic pathway. Then, the viral shell is removed, the viral genomic RNA is released into the cytoplasm, and the translation of the viral polymeric protein begins with the viral genomic RNA as mRNA (Hu et al.2003; Solomon et al.2010). The replication of EV71 is similar to that of other positive-stranded RNA viruses. First, polymeric precursor protein is synthesized by viral RNA as mRNA template. Then, polymer precursor protein is cut into four structural proteins and seven nonstructural proteins. The nonstructural protein 3D, an RNA-dependent RNA polymerase (RdRp), synthesizes negative-chain RNA using RNA as a template. A large number of positive-strand RNAs are further synthesized using negative-strand RNA as a template. With the accumulation of a large number of viral positive-strand RNAs in the cytoplasm, the subgeneration virus particles begin to be assembled (Bedard and Semler 2004).
Function of the Noncoding Region
The 5′ UTR
The 3′ UTR
The 3′ UTR of EV71 contains a variable poly(A) tail, which is very important for EV71 replication. The poly(A) tail in eukaryotic cells can confer mRNA stability, promote the translational efficiency of mRNA, and transport mRNA from the nucleus to the cytoplasm (Weng et al.2009). However, the specific function of the 3′ UTR and poly(A) tail for EV71 is not fully understood, and studies of PV have shown that the recombinant 3′ UTR of PV is active, although its replication rate is slower than that of the wild-type sequence (Fernandez-Miragall et al.2009; Herold and Andino 2001; Silvestri et al.2006; Todd et al.1997). Sim and others have shown that the chemical synthesis of siRNA targeting the 3′ UTR can reduce the replication of EV71. Transfection of rhabdomyosarcoma cells with siRNA targeting the 3′ UTR region significantly decreases viral RNA, viral proteins, and plaque formation; therefore, RNA interference may also be used as a method for clinical antiviral therapy (Sim et al.2005). A recent study showed that miR-23b is significantly downregulated in EV71-infected cells and that upregulation of miR-23b inhibits the replication of EV71 by targeting the EV71 3′ UTR conserved sequence through seven consecutive nucleic acids (Wen et al.2013). Feng et al. found that miR-127-5p expression was upregulated during EV71 infection and miR-127-5p can inhibit EV71 infection through downregulating the expression of SCARB2 via targeting two potential sites in 3′ UTR region (Feng et al.2017).
VP1 is the main virus-neutralizing determinant, directly determining the antigenicity of the virus, and contains the main antigen-binding site (Huang et al.2008). The N-terminal of VP1 capsid protein possesses an important antigen region, which is highly immunogenic. The peptides (amino acids 66–77 or 208–222) of the C-terminal of VP1 capsid protein may stimulate the production of neutralizing antibodies. In addition, three regions on the VP1 protein (amino acids 66–77, 145–159, and 247–261) are capable of inducing human EV-71-specific CD4+ T-cell proliferation (Foo et al.2008). The full-length VP1 is capable of self-association and forms a dimerization structure to improve the pathogenicity of the virus and the ability to adapt to the external environment. VP1 (amino acids 66–132) contains the major dimerization domain, and VP1 (amino acids 132–297) contributes largely to increasing the strength of the interaction (Lal et al.2006).
VP1, a surface antigen, is a suitable candidate for EV71 vaccines. Two peptides, SP55 (amino acids 163–177) and SP70 (amino acids 208–222) are capable of eliciting neutralizing antibodies against EV71. Immunization of mice with either SP55 or SP70 triggers an EV71-specific IgG response as high as that obtained with the whole virion as immunogen; thus, SP70 represents a promising candidate for an effective synthetic peptide-based vaccine against EV71 (Foo et al.2007). Oral immunization with recombinant VP1 protein (rVP1) induces VP1-specific IgA antibodies, serum-specific IgG, and neutralization antibodies in mice and may be a promising subunit vaccine candidate for preventing EV71 infection (Zhang et al.2014). Immunization of hamsters with an EV71 VP1 fragment (NPt-VP11-100) protein can induce good immune responses, but the high level of antibodies fails to neutralize EV71 viruses or protect vaccinated hamsters in viral challenge studies (Ch’ng et al.2012).
The EV71 viral particle capsid composition complex and three structural proteins VP1, VP2, and VP3, which are exposed on the surface of the shell with no homology of nucleotide sequences among them, show certain similarities of the protein topology structure. The VP4 package is embedded in the inside of the virus shell, is closely connected with the virus core, and exhibits an extended spatial conformation feature, which is a bridge connecting the inside and outside (Chen et al. 2010; Rowlands et al.2010). When the virus binds to the receptors, the spatial configuration will change, and the VP4 is lost. Eventually, the viral shell is removed, the viral genomic RNA is released into the cytoplasm, and the translation of the viral polymeric protein begins with the viral genomic RNA as mRNA. The N-terminal myristoylation signal (MGXXXS) of VP4 plays an important role in EV71 replication, and different myristic acid analogs elicit differential effects on EV71 replication in vitro, suggesting that removal of the myristate moiety in the viral structural protein precursor can be an effective antiviral target for further research (Tan et al.2016). EV71 virus capsid proteins VP2 and VP3, which are important parts of the shell protein, are associated with the antigenicity of the virus. Thus, VP2 and VP3 may be potential candidates with structures similar to that of VP1, and VP2 (amino acids 142–146) contains a single, linear, non-neutralizing epitope, which is located in the E–F loop of the VP2 protein (Chen et al.2010; Kiener et al.2012). VP2 149 M mutation enhances viral binding and RNA accumulation of EV71, which promotes EV71 infectivity in vitro and mouse lethality in vivo (Huang et al.2012). T cells play an important role in the host immune response against EV71 infection. Compared with the other three capsid proteins, VP2 shows a more extensive distribution and immunogenicity in T cells (Tan et al.2013). The VP2-28 epitope containing residues 136–150 of VP2 was identified as another neutralizing epitope. Xu et al. (2015) constructed a bivalent chimeric virus-like particle (VLP) presenting the VP1 (amino acids 208–222) and VP2 (amino acids 141–155) epitopes of EV71 that could induce higher IgG titers and neutralization titers and protect neonatal mice against lethal EV71 and CA16 infections. Moreover, they found that anti-VP2 (amino acids 141–155), but not anti-VP1 (amino acids 208–222), could crossreact with normal EV71 and CA16 virions (Xu et al.2015). Kiener et al. (2014) found that the knob of EV71 VP3 encompassing residues 55–69 of VP3 is a new conformational epitope of EV71 involved in EV71 virus neutralization. The importance of this novel neutralization epitope lies in the optimization of putative EV71 vaccines because the VP3 knob can be combined with VP1 to form a bivalent subunit vaccine (Kiener et al.2014).
The EV71 2A protease exhibits cysteine protease activity and contains 150 amino acid residues; it is an enzyme that cleaves at its own N-terminus at the junction between VP1 and 2A of the polyprotein. A polyprotein, translated from the single ORF of EV71, is processed into mature proteins by 2A (Hellen et al.1992; Hsu et al.2007; Ventoso and Carrasco 2003). Eukaryotic translation initiation factor 4G (eIF4G) induces the synthesis of the host cell proteins by promoting the interaction between mRNA and the 40S ribosomal subunit. 2Apro inhibits host cap-dependent protein synthesis by cleaving the elongation factor eIF4G and promoting EV71 replication (Fig. 3) (Morley et al.1997). 2A can block typical stress granule formation and induce atypical stress granule formation by cleaving eIF4GI to sequester cellular mRNA but release viral mRNA, thereby facilitating viral translation (Yang et al.2018). In addition, the 2A protease of EV71 shows great transcription activity in yeast, which is independent of its protease activity. EV71 2A protease retains its transcriptional activity after truncation of 40 amino acids at the N-terminus but loses this activity after truncation of 60 amino acids at the N-terminus or deletion of 20 amino acids at the C-terminus. The acidic structure domain at the C terminal is necessary for its transcriptional activity, and deletion of amino acids 146–149 (EAME) in this acidic domain causes the loss of transcriptional activity (Yang et al.2010).
As shown in Fig. 3, 2A is capable of cleaving FBP1 at the Gly-371 residue of FBP1, which generates a functional cleavage product, FBP11−371. FBP11−371 can bind to the 5′ UTR linker region, which is different from full-length FBP1. Moreover, FBP1 and FBP11−371 act additively to promote IRES-mediated translation and enhance EV71 replication (Hung et al.2016). 2A significantly inhibits cellular endoplasmic reticulum-associated degradation (ERAD) by inhibiting the transcription of the de novo synthesis of key molecules Herp and VIMP. p97, a host factor that is distributed and co-exists with the viral protein and EV71 replication-related molecules, is hijacked from cellular ERAD by EV71 to promote viral replication (Wang et al.2017b).
Type I IFNs (IFN-Is) are key players in the innate antiviral response against viral infections. However, IFN therapy does not significantly affect EV71 infection, and induction of downstream IFN-stimulated genes is inhibited by EV71. The 2A protease can reduce IFN-I receptor protein 1 levels and suppress interferon regulatory factor 3 (IRF3) signaling by cleaving mitochondrial antiviral protein and retinoid acid-inducible gene I (RIG-I)-like receptor MDA5, thus inhibiting IFN signaling pathways and causing the virus to escape the immune response (Fig. 3) (Kuo et al.2013; Lu et al.2012; Wang et al.2013). In addition, 2A attenuates IFN-γ signaling using another mechanism by reducing the serine phosphorylation of signal transducer and activator of transcription 1 (STAT1) following the inactivation of extracellular signal-regulated kinase without affecting STAT1 expression (Fig. 3) (Wang et al.2015b). 2A protein can also induce apoptotic cell death (Kuo et al.2002a). EV71 infection induces the production of inflammasomes, whereas inflammasomes inhibit the replication of EV71. 2A protein can block the production of inflammasomes by eliminating NLRP3 protein at the G493-L494 or Q225-G226 junction (Fig. 3) (Wang et al.2015a).
The 2C protein of EV71 is one of the most highly conserved nonstructural proteins, containing 329 amino acid residues. 2C harbors an adenosine triphosphatase (ATPase) domain, a zinc finger structure, and an alpha helix at the end of the C-terminal region (Guan et al.2017). The 2CATPase, an RNA helicase that 3′-to-5′ unwinds RNA helices in an ATP-dependent manner and an RNA chaperone independently of ATP, facilitates EV71 RNA synthesis in vitro. 2CATPase-mediated RNA remodeling plays a critical role in the EV71 life cycle (Xia et al.2015). The N terminus of the 2C protein, which exhibits both RNA- and membrane-binding activity, interacts with reticulon 3 (RNT3) via its highly conserved reticulon homology domain and then combines with double-stranded RNA (dsRNA) viruses to form viral replication complex and participate in viral replication (Fig. 4). Reduced production of RNT3 by RNA interference markedly reduces the synthesis of EV71-encoded viral proteins and replicative dsRNA, reducing plaque formation and apoptosis (Tang et al.2007). 2C proteins can control the activity of nucleoside triphosphate and participate in the synthesis of negative-strand RNA and the capsid formation of PV subgeneration viral particles (Wu et al.2010a). By interaction with the IPT domain (amino acids 194–290) of p65, 2C can reduce the formation of the heterodimer p65/p50 and then inhibit nuclear factor (NF)-κB activation (Fig. 4) (Du et al.2015). The N-terminal of 2C (amino acids 1–125) interacts with all isoforms of the protein phosphatase 1 (PP1) catalytic subunit through PP1-docking motifs, which is efficient for EV71 2C-mediated inhibition of IKKβ phosphorylation and NF-κB activation (Fig. 4). Moreover, 2C forms a complex with PP1 and IKKβ to dephosphorylate IKKβ activation (Li et al.2016; Zheng et al.2011). Coat protein complex I (COPI) may be directed to the viral replication complex through viral 2C protein to enhance EV71 infection, whereas the inhibition of COPI activity can weaken the replication of EV71 (Fig. 4) (Wang et al.2012a).
The 3B protein, also known as a VPg protein, is a small protein that contains 22 amino acid residues. The VPg protein forms phosphodiester bonds with pUpU at the 5′ UTR of the EV71 genome through the hydroxyl groups of the Try residues and then uses vpg-pUpU as the primer to participate in the synthesis of the negative chain and plus strand RNA (Herrero et al.2003; Liu et al.2007; McMinn 2002). VPg protein can interact with the polymerase 3D, and VPg is catalyzed by 3D polymerase to uridine acidification, which is a primer for viral RNA synthesis (Paul et al.2003).
EV71 3C protease plays an important role in viral replication, and sequence analysis showed that no homologous sequence of EV71 3C is present in mammals; therefore, the 3C protein may be a potential target for antiviral drugs (Kuo et al.2008). 3C can bind to the SUMO E2 conjugating enzyme Ubc9 after binding of the K52 amino acid and SUMO E2 ligase and be SUMO modified at residue K52 for degradation, correlating with a decrease in EV71 in virus replication and cell apoptosis (Fig. 6) (Chen et al.2011). Overexpression of the telomere binding protein PinX1 can inhibit the apoptosis induced by EV71 infection, whereas the 3C protein interacts with PinX1 to degrade PinX1, which can promote host cell apoptosis (Fig. 6) (Li et al.2017). Ubc6e, an E2 ubiquitin-conjugating enzyme, plays a key role in EV71-dependent ERAD disruption, and EV71 3C cleaves Ubc6e at Q219G, Q260S, and Q273G, which can inhibit ERAD to promote EV71 replication (Fig. 6) (Wang et al.2017b). EV71 induces the production of inflammatory cytokines, and 3C interacts with transforming growth factor-β activated kinase 1 (TAK1) and the TAK1 binding protein 1 (TAB 1), which inhibits NF-κB activation. Furthermore, 3C mediates the cleavage of TAK1/TAB 1/TAB 2/TAB 3 complexes to interfere with inflammatory responses (Fig. 6) (Lei et al.2014).
EV71 inhibits antiviral immunity by inhibiting RIG-I to downregulate IFN-β, IFN-stimulated gene 54 (ISG54), ISG56, and TNF in virus-infected cells. The 3C protein can inhibit IFN-β activation by virus and RIG-I but does not inhibit MDA5. 3C is associated with RIG-I via the caspase recruitment domain, which prevents the recruitment of an adaptor IPS-1 and subsequent nuclear translocation of IRF3 (Fig. 6) (Lei et al.2010). In addition, miR-526a positively regulates virus-triggered IFN-I production, thus suppressing viral replication. 3C can inhibit interferon production by downregulating miR-526a or inhibiting interferon regulation factor 7 to block the RIG-I signaling pathway (Lei et al.2013; Xu et al.2014). Toll-like receptor (TLR)-related pathways play an important role in antiviral immune responses. TLR3 in the endosome recognizes viral dsRNA and recruits a TIR domain-containing adaptor inducing IFN-β (TRIF) to transmit signals to IRF3 and NF-κB. 3C is capable of cleaving TRIF and impairing type I IFN production in response to TLR3 activation (Fig. 6) (Lei et al.2011). EV71 infection induces the production of inflammasomes, and the NLRP3 inflammasome plays a protective role against EV71 infection. 3C protein can block the production of the inflammasome by eliminating NLRP3 protein (Fig. 6) (Wang et al.2015a).
The EV71 3D protein, containing 462 amino acid residues, is an RdRp, which mainly completes the extension of the RNA chain during viral replication. The 3D polymerase is indispensable for the initiation of viral replication and plays an important role in changing viral virulence. When 3D is cleaved from 3CD, the nucleic acid location signal of the 3D protein transmits 3CD to the host cell nucleus and shuts down the transcription of the host cell (Wang et al.2010; Wu et al.2010b). The EV71 3D protein is a polymerase dependent on Mn2+, which is completely inactive in the presence of Mg2+. Studies of EV71 transcription activity in vitro have shown that 3D can use dinucleotide and 10-nucleotide RNA as a primer and initiates transcription using genomic RNA as a template (Jiang et al.2011). In addition, the EV71 3D protein attenuates STAT1 tyrosine phosphorylation independent of Janus kinase 2 inactivation, without interfering with IFN-γ receptor expression. Then, 3D blocks IRF1 activation and antagonizes the antiviral activity of IFN-γ (Fig. 5) (Agirre et al.2002). EV71 induces the production of IL-1β through activation of the NLRP3 inflammasome. 3D interacts with NLRP3 to facilitate the assembly of the inflammasome complex by forming a 3D-NLRP3-ASC ring-like structure and then stimulates activation of the NLRP3 inflammasome and the cleavage of pro-caspsase-1, which causes the release of IL-1β (Fig. 5) (Wang et al.2017c).
In summary, different viral proteins of EV71 exert various functions to guarantee the replication of the virus itself. Although some progress has been made in research on the function of the EV71 genome, further studies are still needed. For example, the function of the 3′ UTR is relatively unclear. Notably, however, EV71 infection induces the host immune response, resulting in the expression of many host factors that inhibit EV71 replication through different mechanisms. For example, the promyelocytic leukemia protein contributes to cellular antiviral effects by inhibiting autophagy (Chen et al.2018), and A3G competitively binds to the 5′ UTR to inhibit the 5′ UTR activity of EV71 and the synthesis of EV71 viral proteins and RNA (Li et al.2018b). In the future, researchers will need to focus not only on further structural and functional studies of EV71 proteins but also on how viral virulence factors interact with the human immune system, which will have a profound impact on the development of vaccines and drugs. Such studies will improve our comprehensive understanding of EV71 genome structure and function. This will also help us elucidate the pathogenesis of EV71, which will provide insights into the design of therapeutic strategies against EV71 infection.
The work was supported by the National Natural Science Foundation of China (Grant 81503118) and CAMS Initiative for Innovative Medicine (CAMS-I2 M-1-010); The National Science and Technology Major Project of the Ministry of Science and Technology of China (2018ZX09711003-005-004).
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Conflict of interest
The authors declare that they have no conflict of interest.
Animal and Human Rights Statement
The authors declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.
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