Abstract
Dengue virus (DENV) infection is a significant public health threat in tropical and subtropical regions; however, there is no specific antiviral drug. Accumulated studies have revealed that DENV infection induces several cellular responses, including autophagy and apoptosis. The crosstalk between autophagy and apoptosis is associated with the interactions among components of these two pathways, such as apoptotic caspase-mediated cleavage of autophagy-related proteins. Here, we show that DENV-induced autophagy inhibits early cell apoptosis and hence enhances DENV replication. Later, the apoptotic activities are elevated to suppress autophagy through cleavage of Beclin-1, an essential autophagy-related protein. Inhibition of cleavage of Beclin-1 by a pan-caspase inhibitor, Z-VAD, increases both autophagy and viral replication. Regarding the mechanism, we further found that DENV nonstructural protein 1 (NS1) is able to interact with Beclin-1 during DENV infection. The interaction between Beclin-1 and NS1 attenuates Beclin-1 cleavage and facilitates autophagy to prevent cell apoptosis. Our study suggests a novel mechanism whereby NS1 preserves Beclin-1 for maintaining autophagy to antagonize early cell apoptosis; however, elevated caspases trigger apoptosis by degrading Beclin-1 in the late stage of infection. These findings suggest implications for anti-DENV drug design.
Highlights
Dengue disease is caused by dengue virus (DENV) infection, and it places a heavy socioeconomic and disease burden on many tropical and subtropical regions [1]
Cells were harvested from 3 concomitant infections, and expressions of the following were determined by Western blot: LC3-II as a surrogate for autophagosome accumulation; p62 as a surrogate for ubiquitinated protein sequestration; and caspase-3 as a marker of apoptosis
These results suggest that Dengue virus (DENV) induces autophagy to inhibit early cell apoptosis and help DENV replication
Summary
Dengue disease is caused by dengue virus (DENV) infection, and it places a heavy socioeconomic and disease burden on many tropical and subtropical regions [1]. For the development of antiviral drugs, viral factors and cellular factors, which are required for the replication of DENV, are important targets [3,4]. Some reports have demonstrated that the autophagic machinery activated by DENV infection is able to enhance its replication [6,10,11,12,13]. In another way, apoptosis is a process of programmed cell death that regulates cellular homeostasis by removing damaged, infected, or excess amounts of cells. DENV has been found to develop certain strategies to inhibit apoptosis in the early life cycle to ensure viral replication. Our current study further pointed out that the PI3K/Akt pathway and 78-kDa glucose-regulated protein/Binding immunoglobulin protein (GRP78/Bip) are both required for DENV early replication [20]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
