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生长停滞与DNA损伤蛋白45A通过下调TBK1表达促进小反刍兽疫病毒复制,以抑制IFN-β信号通路。

Growth Arrest and DNA Damage Protein 45A Promotes PPRV Replication via the Downregulation of TBK1 Expression to Inhibit IFN-β Signaling Pathway.

作者信息

Ding Haiyan, Yang Wenping, Wu Jinyan, Wu Junhuang, Wang Mengyi, He Jijun, Yuan Ligang, Zheng Haixue, Shang Youjun, Li Dan

机构信息

State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China.

Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China.

出版信息

FASEB J. 2025 Jun 30;39(12):e70741. doi: 10.1096/fj.202500364R.


DOI:10.1096/fj.202500364R
PMID:40548900
Abstract

Peste des petits ruminants virus (PPRV) is a highly contagious pathogen that severely impacts goats and sheep due to its high contagiousness and pathogenicity. Viruses rely on host proteins for their pathogenicity and replication, but the specific mechanisms facilitating PPRV replication by host proteins remain poorly understood. In this study, we identified goat growth arrest and DNA damage protein 45A (GADD45A) as a positive regulator of PPRV replication. Overexpression of GADD45A enhances PPRV replication, while its knockdown significantly inhibits PPRV replication. Furthermore, GADD45A suppresses SeV- or Poly(I:C)-induced IFN-β promoter and ISRE activation in a dose-dependent manner, as well as the transcription of interferon-stimulated genes (ISGs). We also demonstrate that goat GADD45A interacts with TANK-binding kinase 1 (TBK1), leading to the downregulation of TBK1 expression. Co-immunoprecipitation and confocal microscopy confirmed that GADD45A interacts with the PPRV V protein. Both GADD45A and V synergistically inhibit IFN-β promoter activation and TBK1 expression, thereby promoting PPRV replication. Our findings suggest that GADD45A promotes PPRV replication by downregulating TBK1, offering new insights into host proteins that counteract innate immune responses during PPRV infection. These findings offer valuable insights into the role of host proteins in viral replication and immune evasion, shedding new light on how PPRV antagonizes innate immunity.

摘要

小反刍兽疫病毒(PPRV)是一种高度传染性的病原体,因其高传染性和致病性而对山羊和绵羊造成严重影响。病毒的致病性和复制依赖于宿主蛋白,但其通过宿主蛋白促进PPRV复制的具体机制仍知之甚少。在本研究中,我们鉴定出山羊生长停滞和DNA损伤蛋白45A(GADD45A)是PPRV复制的正向调节因子。GADD45A的过表达增强了PPRV的复制,而其敲低则显著抑制了PPRV的复制。此外,GADD45A以剂量依赖的方式抑制仙台病毒(SeV)或聚肌苷酸-聚胞苷酸(Poly(I:C))诱导的IFN-β启动子和干扰素刺激反应元件(ISRE)的激活,以及干扰素刺激基因(ISGs)的转录。我们还证明山羊GADD45A与TANK结合激酶1(TBK1)相互作用,导致TBK1表达下调。免疫共沉淀和共聚焦显微镜证实GADD45A与PPRV V蛋白相互作用。GADD45A和V蛋白协同抑制IFN-β启动子激活和TBK1表达,从而促进PPRV复制。我们的研究结果表明,GADD45A通过下调TBK1促进PPRV复制,为PPRV感染期间对抗先天免疫反应的宿主蛋白提供了新见解。这些发现为宿主蛋白在病毒复制和免疫逃逸中的作用提供了有价值的见解,为PPRV如何拮抗先天免疫提供了新线索。

相似文献

[1]
Growth Arrest and DNA Damage Protein 45A Promotes PPRV Replication via the Downregulation of TBK1 Expression to Inhibit IFN-β Signaling Pathway.

FASEB J. 2025-6-30

[2]
Peste des Petits Ruminants Virus Nucleocapsid Protein Inhibits Beta Interferon Production by Interacting with IRF3 To Block Its Activation.

J Virol. 2019-7-30

[3]
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[4]
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J Virol. 2024-4-16

[5]
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J Immunol. 2021-2-1

[6]
Peste des petits ruminants virus non-structural C protein inhibits the induction of interferon-β by potentially interacting with MAVS and RIG-I.

Virus Genes. 2021-2

[7]
Structure, Attachment and Transmembrane Internalisation of Peste Des Petits Ruminants Virus.

Vet Med Sci. 2025-1

[8]
Peste Des Petits Ruminants in Atypical Hosts and Wildlife: Systematic Review and Meta-Analysis of the Prevalence between 2001 and 2021.

Arch Razi Inst. 2021-12

[9]
The Nucleoprotein and Phosphoprotein of Peste des Petits Ruminants Virus Inhibit Interferons Signaling by Blocking the JAK-STAT Pathway.

Viruses. 2019-7-8

[10]
STING-ΔN, a novel splice isoform of STING, modulates innate immunity and autophagy in response to DNA virus infection.

Cell Commun Signal. 2025-6-21

本文引用的文献

[1]
Nifuratel Induces Triple-Negative Breast Cancer Cell G2/M Phase Block and Apoptosis by Regulating GADD45A.

Pharmaceuticals (Basel). 2024-9-26

[2]
Aristolochic acids-hijacked p53 promotes liver cancer cell growth by inhibiting ferroptosis.

Acta Pharmacol Sin. 2025-1

[3]
Bunyavirus SFTSV NSs utilizes autophagy to escape the antiviral innate immune response.

Autophagy. 2024-10

[4]
Activation of the MEK/ERK Pathway Mediates the Inhibitory Effects of Silvestrol on Nasopharyngeal Carcinoma Cells via RAP1A, HK2, and GADD45A.

Front Biosci (Landmark Ed). 2024-4-23

[5]
Enteric coronavirus nsp2 is a virulence determinant that recruits NBR1 for autophagic targeting of TBK1 to diminish the innate immune response.

Autophagy. 2024-8

[6]
Vimentin inhibits peste des petits ruminants virus replication by interaction with nucleocapsid protein.

Virology. 2024-7

[7]
OsGADD45a1: a multifaceted regulator of rice architecture, grain yield, and blast resistance.

Plant Cell Rep. 2024-3-10

[8]
Plasminogen activator urokinase interacts with the fusion protein and antagonizes the growth of Peste des petits ruminants virus.

J Virol. 2024-4-16

[9]
The aldehyde dehydrogenase ALDH1B1 exerts antiviral effects through the aggregation of the adaptor MAVS.

Sci Signal. 2024-1-9

[10]
Peste des petits ruminants virus non-structural V and C proteins interact with the NF-κB p65 subunit and modulate pro-inflammatory cytokine gene induction.

J Gen Virol. 2023-10

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