DDX3X Is Hijacked by Snakehead Vesiculovirus Phosphoprotein To Facilitate Virus Replication via Stabilization of the Phosphoprotein
DDX3X Is Hijacked by Snakehead Vesiculovirus Phosphoprotein To Facilitate Virus Replication via Stabilization of the Phosphoprotein
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DOI：
10.1128/jvi.00035-23
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发表时间：
2023-02-06
影响因子：
5.4
通讯作者：
Tu，Jiagang
中科院分区：
文献类型：
--
作者：
Bei，Congran;Zhang，Chu;Tu，Jiagang
Asp-Glu-Ala-Asp（DEAD）box helicase 3 X-linked（DDX 3X）在许多病毒的复制过程中起着重要的调控作用。然而，DDX 3X在弹状病毒复制中的作用很少被研究。本研究以鱼类弹状病毒--黑鱼水疱病毒（snakehead vesiculovirus，SHVV）为材料，研究DDX 3X在病毒复制中的作用。DDX 3X被鉴定为SHVV磷蛋白（P）的相互作用伴侣。DDX 3X基因在SHVV感染早期表达水平升高，感染后期表达水平下降至正常水平。DDX 3X的过表达促进SHVV复制，而使用特异性小干扰RNA（siRNA）敲低DDX 3X抑制SHVV复制，表明DDX 3X是SHVV复制的前病毒因子。DDX 3X的N-末端和核心结构域（DDX 3X-N和DDX 3X-Core）被确定为负责其与SHVV P相互作用的区域。DDX 3X-Core的过表达通过竞争性破坏全长DDX 3X和SHVV P之间的相互作用来抑制SHVV复制，这表明全长DDX 3X-P相互作用是SHVV复制所需的。从机制上讲，DDX 3X介导的SHVV复制的促进不是由于干扰素表达的抑制，而是由于维持SHVV P的稳定性以避免自噬溶酶体依赖性降解。总的来说，我们的数据表明DDX 3X被SHVV P劫持以确保SHVV的有效复制，这表明了重要的抗SHVV靶标。本研究将有助于阐明DDX 3X在调节弹状病毒复制中的作用。重要意义越来越多的证据表明DDX 3X在病毒复制中起重要作用。在一个方面，DDX 3X抑制病毒的复制，包括B型肝炎病毒、甲型流感病毒、纽卡斯尔病病毒、鸭坦布苏病毒和红斑石斑鱼神经坏死病毒。在另一方面，DDX 3X是病毒复制所必需的，所述病毒包括丙型肝炎病毒、日本脑炎病毒、西尼罗河病毒、鼠诺如病毒、单纯疱疹病毒和严重急性呼吸综合征冠状病毒2（SARS-CoV-2）。由于DDX 3X在弹状病毒复制中的研究很少，本研究旨在以鱼类弹状病毒SHVV为模型研究DDX 3X在弹状病毒复制中的作用。我们发现DDX 3X是SHVV复制所必需的，其机制是DDX 3X与SHVV磷蛋白相互作用并维持其稳定性。我们的数据为DDX 3X在病毒复制中的作用提供了新的见解，并将促进抗弹状病毒感染的抗病毒药物的设计。
Asp-Glu-Ala-Asp (DEAD) box helicase 3 X-linked (DDX3X) plays important regulatory roles in the replication of many viruses. However, the role of DDX3X in rhabdovirus replication has seldomly been investigated. In this study, snakehead vesiculovirus (SHVV), a kind of fish rhabdovirus, was used to study the role of DDX3X in rhabdovirus replication. DDX3X was identified as an interacting partner of SHVV phosphoprotein (P). The expression level of DDX3X was increased at an early stage of SHVV infection and then decreased to a normal level at a later infection stage. Overexpression of DDX3X promoted, while knockdown of DDX3X using specific small interfering RNAs (siRNAs) suppressed, SHVV replication, indicating that DDX3X was a proviral factor for SHVV replication. The N-terminal and core domains of DDX3X (DDX3X-N and DDX3X-Core) were determined to be the regions responsible for its interaction with SHVV P. Overexpression of DDX3X-Core suppressed SHVV replication by competitively disrupting the interaction between full-length DDX3X and SHVV P, suggesting that full-length DDX3X-P interaction was required for SHVV replication. Mechanistically, DDX3X-mediated promotion of SHVV replication was due not to inhibition of interferon expression but to maintenance of the stability of SHVV P to avoid autophagy-lysosome-dependent degradation. Collectively, our data suggest that DDX3X is hijacked by SHVV P to ensure effective replication of SHVV, which suggests an important anti-SHVV target. This study will help elucidate the role of DDX3X in regulating the replication of rhabdoviruses.IMPORTANCEGrowing evidence has suggested that DDX3X plays important roles in virus replication. In one respect, DDX3X inhibits the replication of viruses, including hepatitis B virus, influenza A virus, Newcastle disease virus, duck Tembusu virus, and red-spotted grouper nervous necrosis virus. In another respect, DDX3X is required for the replication of viruses, including hepatitis C virus, Japanese encephalitis virus, West Nile virus, murine norovirus, herpes simplex virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Because DDX3X has rarely been investigated in rhabdovirus replication, this study aimed at investigating the role of DDX3X in rhabdovirus replication by using the fish rhabdovirus SHVV as a model. We found that DDX3X was required for SHVV replication, with the mechanism that DDX3X interacts with and maintains the stability of SHVV phosphoprotein. Our data provide novel insights into the role of DDX3X in virus replication and will facilitate the design of antiviral drugs against rhabdovirus infection.