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Figure 1. The structure of the flavivirus genome. The protein is cleaved co- and post-translationally to form capsid (C), membrane (M) and envelope (E) structural proteins and nonstructural proteins (NS)-1, 2A, 2B, 3, 4A, 4B and 5.
Figure 2. The Flavivirus life cycle. 1) The viruses attach to the surface of a host cell and internalize by receptor-mediated endocytosis. 2) Acidification of the endosomal vesicle triggers conformational changes in the virion, fusion of the viral envelope and cell membranes, releasing the viral genome into the cytoplasm. 3) The positive-sense RNA is translated into a single polyprotein that is processed co- and post-translationally by viral and host proteases. The viral RNA-dependent RNA polymerase replicates the viral genome in specialized ER-derived membrane compartments. 4) Virus assembly occurs on the surface of the ER, the immature viral particles bearing prM and E bud into ER rumen after nucleocapsid formation with viral RNA. The resultant non-infectious, immature viral are transported to the trans-Golgi network (TGN). 5) The host protease furin cleaved of prM to M, generating mature infectious particles. 6) Mature virions are subsequently released by exocytosis.
Figure 3. The intrinsic apoptotic pathway. The intrinsic cell death pathway is activated by an intracellular death signal. (a) This signal results in the oligomerization and translocation of Bak and Bax into the outer membrane of the mitochondria. This triggers mitochondrial outer membrane permeabilization (MOMP) and the release of Cyt-c and IAP binding proteins. Cyt-c forms a complex with pro-caspase-9 and Apaf-1, leading to activation of caspase-9, then caspase-9 activates the executioner caspases (caspase-3, -6, and -7) and induces cell death. The IAP binding proteins, such as Diablo and HtrA2, enhance caspase activation through the neutralization of IAPs. (b) Under ER stress, three upstream signaling proteins, IRE1, PERK and ATF6, are activated, thus leading to a cascade of activity that induces apoptosis. (b1) The prolonged activation of IRE1 can promote apoptosis. Phosphorylated IRE1 recruits TRAF2 and triggers a cascade of phosphorylation events, such as the activation of ASK1, which ultimately phosphorylates and activates JNK. Then, JNK phosphorylation activates pro-apoptotic genes and induces apoptosis through the mitochondrial pathway. (b2) The homomultimerization and autophosphorylation of PERK leads to eIF-2α phosphorylation, which increases the translation of ATF4. Then, ATF4 upregulates the expression of CHOP, which promotes apoptosis. (b3) ATF6 migrates to the Golgi apparatus to undergo cleavage, first by S1P and then by S2P, cleaved ATF6 can also promote apoptosis via upregulation of CHOP.
Figure 4. The extrinsic apoptotic pathway. The extrinsic pathway is activated by death signals mediated by death ligands. (a) Fas and DR4/5 are activated by the binding of their respective ligands FasL and TRAIL; the receptors then bind to FADD via the DD. Then, the DED of FADD binds to procaspase-8/10, which forms a complex called the DISC and sends a signal to activate caspase-8 and -10, then caspase-8 and -10 induce the activation of the caspase cascade and ultimately results in apoptosis. (b) In particular cells, the extrinsic pathway crosstalks with the intrinsic pathway through caspase-8-mediated truncation of Bid to tBid. tBid activates BAK/BAX oligomerization and induces apoptosis through the mitochondrial pathway. (c) TNFR1 is activated by the binding of its respective ligand TNFα. TNFR1 recruits TRADD, an adaptor protein that binds to TRAFs, RIP1 and IAPs, forming the initial membrane complex (complex I), which stimulates the NF-κB pathways to facilitate apoptosis. (d) Complex I forms two types of cytoplasmic apoptotic complexes, TRADD-dependent complex IIA and RIP1-dependent complex IIB, which activate caspase-8, thus initiating apoptosis.