3.1.2 Regulation of DENV proteins on apoptosis
Limjindaporn et al.(Limjindaporn et al.,
2007) confirmed that the DENV2 capsid protein (DENV2-C) physically
interacts with death protein 6
(Daxx), a human death domain-associated protein, and the nuclear
localization of DENV2-C is closely related to DAXX interaction and
apoptosis induction, elucidating the pro-apoptotic function of
DENV2-C(Netsawang et al., 2010).
Moreover, DENV2-C promotes the release of NF-κB by binding Daxx, which
usually interacts with NF-κB. Since
NF-κB
can activate CD137 promoter, the interaction between CD137 ligand and
CD137 eventually activates caspase cascades and apoptosis, indicating
that NF-κB signal contributes to DENV2-C-induced
apoptosis(Nagila et al., 2011). Cell
death gene RIPK2
(receptor-interacting serine/threonine protein kinase 2), is a key
mediator of various stress responses, leading to the activation of
NF-κB, MAPK and caspases. The expression of RIPK2 contributes to
apoptosis induced by capsid protein but only for DENV-2 and -4
serotypes(Atthapan Morchang et al.,
2011). There is evidence that the M proteins of four DENV serotypes can
trigger the intrinsic apoptosis pathway in host cells such as Neuro 2a
and HepG2 cells, and the nine carboxy-terminal amino acids (residues
M-32 to M-40) of M protein called ApoptoM is cytotoxic and directly
involved. In addition, the M ectodomains of JEV, WNV and YFV also have
pro-apoptotic effects, indicating that the M protein plays a key role in
determining the fate of flavivirus-infected
cells(Catteau et al., 2003). Another
study found that DENV2-envelope protein domain III (DENV2-EIII)
suppresses megakaryopoiesis by inducing apoptosis of differentiated
Megakaryocytes (MKs), which is one
of the causes of thrombocytopenia(G.-L.
Lin et al., 2017). Therefore, DENV2-EIII can be used as a drug target
to for the treatment of MKs deficiency and thrombocytopenia in severe
dengue.
Subsequently, Ochoa et al.(Ochoa et al.,
2009) found that human
microvascular endothelial cells (HMEC-1) transfected with DENV2 serine
protease NS3 or NS2B-NS3 complex can trigger apoptosis. Further study
have shown that NS3 activates NF-κB by inducing IκBα/IκBβ cleavage and
activating IκB kinase, which triggers the extrinsic apoptotic
pathway(J.-C. Lin et al., 2014).
Moreover, NS2B-NS3 caused a higher proportion of apoptosis, indicating
that NS2B is an important cofactor for NS3 to induce
apoptosis(Shafee & AbuBakar, 2003).
Interestingly, DENV-2 NS5 can also translocate into nucleus and interact
with Daxx to further increase the production of RANTES. Therefore, NS5
may have a similar apoptosis-inducing function to DENV2-C, but this
requires further experimental
verification(Khunchai et al., 2012;
Nagila et al., 2011).