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).