Figure legend
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.