Phenazine biosynthesis-like domain-containing protein (PBLD) and Cedrelone promote antiviral immune response by activating NF-ĸB

• Published in: Nature communications 2025-01, Vol.16 (1), p.496-18, Article 496
• Main Authors: Hou, Peili, Zhu, Hongchao, Chu, Fengyun, Gao, Yan, Sun, Xiaonan, Zhang, Fuzhen, Wang, Xiaomeng, Feng, Yueyue, Li, Xingyu, Liu, Yu, Wang, Jun, Wang, Xiaoyun, He, Daniel Chang, Wang, Hongmei, He, Hongbin
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/31; 13/95; 14/19; 38; 42; 45; 49; 59; 631/250/2504/342; 631/250/255/2514; 631/250/262; 631/326/596/2553; 64; 64/86; 96; Animals; Antiviral agents; Antiviral Agents - pharmacology; Antiviral drugs; Biosynthesis; Cell survival; Chemotherapy; Cyclohexanones - pharmacology; Drug therapy; Female; HEK293 Cells; Herpes Simplex - drug therapy; Herpes Simplex - immunology; Herpes Simplex - virology; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - immunology; Humanities and Social Sciences; Humans; I-kappa B Kinase - metabolism; Immune response; Immune system; Infections; Interferon; Interferon Type I - immunology; Interferon Type I - metabolism; Intracellular Signaling Peptides and Proteins; Kinases; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; NF-kappa B - metabolism; NF-κB protein; Phenazine; Phenazines - pharmacology; Protein biosynthesis; Proteins; Replication; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Suppressors; Tumor suppression; Tumors; Viral infections; Virus Replication - drug effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54882-y

Phenazine biosynthesis-like domain-containing protein (PBLD) and Cedrelone have been identified as tumor suppressors. However, their roles in virus infection remain unclear. Here, we demonstrate that PBLD upregulates the type I interferon (IFN-I) response through activating NF-kappaB (NF-κB) signaling pathway to resist viral infection in cells and mice. Mechanistically, PBLD activates NF-κB signaling pathway during viral infection via blocking tripartite motif containing 21 (TRIM21)-mediated phosphorylated inhibitory kappa B kinase beta (IKKβ) degradation. Furthermore, we show Cedrelone inhibits viral replication by increasing the PBLD protein expression and subsequently activating NF-κB-mediated IFN-I response. Furthermore, the therapeutic potential of Cedrelone lies in its ability to enhance antiviral immunity in primary macrophages and to promote survival and reduce lung tissue damage in HSV-1-infected mice in a PBLD-dependent manner. Consequently, our findings provide a potential combination model that targets PBLD for Cedrelone antiviral drug therapy, potentially paving the way for the development of broad-spectrum antiviral agents. Phenazine biosynthesis-like domain-containing protein (PBLD) and cedrelone play roles in tumor suppression. Here, authors suggest that PBLD and Cedrelone inhibit viral replication via activating the NF-κB-mediated IFN-I signaling response in cells and mice.