Coordinated regulation of autophagy and apoptosis determines endothelial cell fate during Dengue virus type 2 infection

Abstract

Dengue is the most prevalent mosquito-borne viral disease in tropical regions. Severe cases may progress to Dengue hemorrhagic fever, suggesting vascular endothelial dysfunction in disease pathogenesis. In our previous study, we found that Dengue virus type 2 (DENV2) induced apoptosis of vascular endothelial cells via FasL/Fas- and XIAP-associated factor 1 (XAF1)-dependent pathways. In this paper, we demonstrate that DENV2 can induce autophagy in primary human umbilical vein endothelial cells (HUVECs) and the human umbilical vein endothelial cell line EA.hy926. Inhibition of autophagy with 3-methyl adenine promoted apoptosis, while inhibition of apoptosis with Z-VAD-FMK facilitated autophagy in DENV2-infected HUVECs and EA.hy926 cells. Interferon-alpha-inducible protein 6 (IFI6), a putative apoptosis regulator, inhibited DENV2-induced autophagy in EA.hy926 cells, while XAF1, an inhibitor of anti-apoptotic XIAP, facilitated autophagy. Molecular regulators of apoptosis and autophagy interact at multiple levels to determine cell fate. Our data suggest that XAF1 and IFI6 are involved in regulating the balance between autophagy and apoptosis in DENV2-infected endothelial cells.

A CRISPR Activation Screen Identifies Genes That Protect against Zika Virus Infection

“…Part of our results are in line with this mechanism and support an antiviral role for IFI6 at an early stage in the viral life cycle occurring at the ER; this is suggested by the localization of the protein and the fact that there was no dsRNA formed in infected cells with activated IFI6. However, we have also confirmed a previously described reduction in cell death following infection of IFI6-or IFN-2-activated cells with ZIKV at later time points (31,32). These results point to an interesting possibility that when expressed before infection, such as in cells surrounding the infected cell following paracrine interferon secretion, these genes can prevent infection.…”

“…IFI6 and IFN-2 activation inhibits cell death in ZIKV-infected cells. IFI6 was previously reported to inhibit apoptosis in DENV-infected cells (31,32), in the context of parvovirus infection (37), and in cancer cells (38)(39)(40). Our results ( Fig.…”

“…3A). IFI6 was previously reported to localize to the mitochondria and to inhibit apoptosis in DENV-infected cells (31,32). To confirm the localization of IFI6, we constructed a C-terminal FLAG fusion protein.…”

Analysis of tick-borne encephalitis virus-induced host responses in human cells of neuronal origin and interferon-mediated protection

“…We identified two genes that were highly up-regulated in IFN-b-treated DAOY cells, in the absence or presence of TBEV, IFI6 and IFI27. They belong to the FAM14 family of ISGs [72] and were documented as mitochondrial proteins involved in apoptosis regulation [73][74][75]. Over-expression of IFI6 inhibited DENV-induced apoptosis of endothelial cells [74,75] and restricted HCV replication in hepatocarcinoma cells [76].…”

Detachment‐Based Equilibrium of Anoikic Cell Death and Autophagic Cell Survival Through Adaptor Protein p66Shc

“…As previously reported, adenovirus vector‐mediated XAF1 can induce autophagy through the inhibition of Akt/p70S6K and upregulation of Beclin 1 in gastric cancer cells (Sun et al, ). Overexpression of XAF1 accelerates autophagy and mitigates endothelial cell apoptosis during dengue virus type 2 infection (Huang et al, ). Therefore, considering the role of p66 Shc in regulating detachment‐induced autophagy, XAF1 may involve in this process to increase the potential of autophagy and cell death.…”