Activation of Host Cellular Signaling and Mechanism of Enterovirus 71 Viral Proteins Associated with Hand, Foot and Mouth Disease

Figure 1. Invasion and replication of EV71 inside the host cell. EV71 attaches to cell surface receptors, co-receptors or other proteins. Endophilin binds to the cytoplasmic motif of activated receptors with SH3 domain and mediates the formation of endocytic carrier with actin polymerization and dynamin. The mechanism of immunogenic evasion of EV71 is based on the conformational changes in the antigen structure. A single polyprotein is produced by IRES-driven translation which is then cleaved into proteins by proteolysis.

Figure 2. EV71-induced JNK-mediated apoptosis pathway inhibited by PI3K/Akt activation through phosphorylating and negatively regulating ASK1.

Figure 3. A graphical illustration of the role of each protein in EV71-induced signaling pathways. By directly interacting and activating the pro-apoptotic protein Bax, 2B triggers cell apoptosis. The overexpression of anti-apoptotic protein Bcl-XL prevents 2B-induced caspase activation and cytochrome C release. 2C protein exhibits both RNA and membrane-binding activity, interacts with reticulon 3 (RNT3), then combines with double-stranded RNA viruses to form a viral replication complex and participates in viral replication. By interacting with 3A protein, the Golgi protein acylcoenzyme A binding domain-containing 3 (ACBD3) facilitates EV71 replication, and triggers the generation of IL-1β by activating NLRP3 inflammasome.

Figure 4. Evasion of PRRsmediated signaling pathways by EV71. By means of the non-structural proteins 2A, 2C, and 3C, EV targets the PRRs signaling pathway. 2A degrades IFNAR1 and cleaves MAVS and MDA5. RIG-1 and MAVS complex is cleavedby 3C which also inactivates TRIF. The activation of RIG-1 bymir-526a is inhibited by 3C and by promoting the expression of miR-146a.