Lu Zi-Yi, Cheng Miao-Huei, Yu Chia-Yi, Lin Yee-Shin, Yeh Trai-Ming, Chen Chia-Ling, Chen Chien-Chin, Wan Shu-Wen, Chang Chih-Peng
Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung 824, Taiwan.
Int J Mol Sci. 2020 Dec 19;21(24):9702. doi: 10.3390/ijms21249702.
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.
登革病毒（DENV）感染是热带和亚热带地区的重大公共卫生威胁；然而，目前尚无特效抗病毒药物。越来越多的研究表明，DENV感染会引发多种细胞反应，包括自噬和凋亡。自噬与凋亡之间的相互作用与这两条途径的组成成分之间的相互作用有关，例如凋亡半胱天冬酶介导的自噬相关蛋白的切割。在此，我们表明DENV诱导的自噬抑制早期细胞凋亡，从而增强DENV复制。随后，凋亡活性升高，通过切割一种重要的自噬相关蛋白Beclin-1来抑制自噬。泛半胱天冬酶抑制剂Z-VAD对Beclin-1切割的抑制作用增加了自噬和病毒复制。关于其机制，我们进一步发现DENV非结构蛋白1（NS1）在DENV感染期间能够与Beclin-1相互作用。Beclin-1与NS1之间的相互作用减弱了Beclin-1的切割，并促进自噬以防止细胞凋亡。我们的研究提出了一种新机制，即NS1通过保留Beclin-1来维持自噬，以对抗早期细胞凋亡；然而，在感染后期，升高的半胱天冬酶通过降解Beclin-1触发细胞凋亡。这些发现为抗DENV药物设计提供了启示。
