Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan, Shandong, China.
Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, China.
Cell Death Dis. 2024 Oct 3;15(10):727. doi: 10.1038/s41419-024-07083-w.
Recent studies have implicated the phenazine biosynthesis-like domain-containing protein (PBLD) in the negative regulation of the development and progression of various cancers. However, its function in viral infection remains unknown. In this study, we found that PBLD plays important roles in multiple virus infections including BPIV3, SeV, VSV, and HSV-1. Our study revealed that PBLD enhances the expression of type I interferon (IFN-I) and ISGs through interferon regulatory factor 3 (IRF3). Further study indicated that PBLD promotes transcriptional phosphorylation of IRF3 (S385/386), thereby facilitating virus-induced IFN-I production. Interestingly, PBLD mediates virus-triggered mitochondrial apoptosis through its dependence on IRF3 (K313/315). Mechanistically, PBLD facilitated virus-induced apoptosis by recruiting the Puma protein to the mitochondria via IRF3. Additionally, we performed mutational analyses of IRF3, showing that its loss of either transcriptional or apoptotic function markedly increased viral replication. Moreover, macrophages with PBLD deficiency during viral infection exhibited decreased the IFN-I and ISGs expression, exacerbating viral infection. Importantly, mice deficient in PBLD exhibited increased viral replication and susceptibility to SeV infection, leading to decreased survival. Notably, Cedrelone, a chemical activator of PBLD, has the ability to reduce SeV replication. Collectively, we first discovered the new function of PBLD in viral infection, broadening our understanding of potential therapeutic targets and offering new insights for antiviral drug development.
最近的研究表明，吩嗪生物合成样结构域蛋白（PBLD）在多种癌症的发展和进展的负调控中起作用。然而，它在病毒感染中的功能尚不清楚。在这项研究中，我们发现 PBLD 在包括 BPIV3、SeV、VSV 和 HSV-1 在内的多种病毒感染中发挥重要作用。我们的研究表明，PBLD 通过干扰素调节因子 3（IRF3）增强 I 型干扰素（IFN-I）和 ISGs 的表达。进一步的研究表明，PBLD 促进了 IRF3 的转录磷酸化（S385/386），从而促进了病毒诱导的 IFN-I 产生。有趣的是，PBLD 通过其对 IRF3 的依赖性（K313/315）介导病毒触发的线粒体凋亡。在机制上，PBLD 通过 IRF3 将 Puma 蛋白募集到线粒体，从而促进病毒诱导的凋亡。此外，我们对 IRF3 进行了突变分析，结果表明其转录或凋亡功能的丧失显著增加了病毒复制。此外，在病毒感染期间缺乏 PBLD 的巨噬细胞表现出 IFN-I 和 ISGs 表达减少，从而加重了病毒感染。重要的是，缺乏 PBLD 的小鼠表现出病毒复制增加和对 SeV 感染的易感性增加，导致存活率降低。值得注意的是，Cedrelone，一种 PBLD 的化学激活剂，具有降低 SeV 复制的能力。总之，我们首次发现了 PBLD 在病毒感染中的新功能，拓宽了我们对潜在治疗靶点的理解，并为抗病毒药物的开发提供了新的思路。
