PBLD promotes IRF3 mediated the type I interferon (IFN-I) response and apoptosis to inhibit viral replication

• Published in: Cell death & disease 2024-10, Vol.15 (10), p.727-20, Article 727
• Main Authors: Zhu, Hongchao, Hou, Peili, Chu, Fengyun, Li, Xingyu, Zhang, Wenjia, Sun, Xiaonan, Liu, Yu, Zhao, Guimin, Gao, Yuwei, He, Daniel Chang, Wang, Hongmei, He, Hongbin
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/2; 13/31; 13/89; 13/95; 14/19; 38/22; 38/23; 38/70; 38/77; 631/154/152; 631/250/1933; 631/80/82/23; 64/60; 82/80; 96/10; 96/95; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Drug development; HEK293 Cells; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - physiology; Humans; Immunology; Infections; Interferon; Interferon regulatory factor; Interferon regulatory factor 3; Interferon Regulatory Factor-3 - metabolism; Interferon Type I - metabolism; Life Sciences; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - drug effects; Mitochondria - metabolism; Phosphorylation; Protein biosynthesis; Proto-Oncogene Proteins; Replication; Signal Transduction - drug effects; Therapeutic targets; Viral infections; Virus Replication - drug effects; Viruses
• ISSN: 2041-4889; 2041-4889
• 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.