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

Peili Hou, Hongchao Zhu, Fengyun Chu, Yan Gao, Xiaonan Sun, Fuzhen Zhang, Xiaomeng Wang, Yueyue Feng, Xingyu Li, Yu Liu, Jun Wang, Xiaoyun Wang, Daniel Chang He, Hongmei Wang () and Hongbin He ()
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Peili Hou: Shandong Normal University
Hongchao Zhu: Shandong Normal University
Fengyun Chu: Shandong Normal University
Yan Gao: Shandong Normal University
Xiaonan Sun: Shandong Normal University
Fuzhen Zhang: Shandong Agricultural University
Xiaomeng Wang: Shandong Normal University
Yueyue Feng: Shandong Normal University
Xingyu Li: Shandong Normal University
Yu Liu: Shandong Normal University
Jun Wang: Shandong Normal University
Xiaoyun Wang: Shandong Normal University
Daniel Chang He: University of North Carolina at Chapel Hill
Hongmei Wang: Shandong Normal University
Hongbin He: Shandong Normal University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-024-54882-y

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