β-Catenin-Specific Inhibitor, iCRT14, Promotes BoHV-1 Infection-Induced DNA Damage in Human A549 Lung Adenocarcinoma Cells by Enhancing Viral Protein Expression

Ding, Xuezhi; Yuan, Weifeng; Yang, Hao; Liu, Chang; Li, Shitao; Zhu, Liqian

doi:10.3390/ijms23042328

Cited by 4 publications

(3 citation statements)

References 33 publications

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“…Prior investigations have also emphasized similar results in case of certain viruses, such as the influenza virus, HSV-1, and SARS-CoV-2 where iCRT14 treatment reduced viral infections ( 12 , 17 , 25 ) . On the contrary, inhibition of β-catenin by iCRT14 increased the expression of certain viral proteins in bovine herpesvirus type 1 ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Chikungunya virus perturbs the Wnt/β-catenin signaling pathway for efficient viral infection

Chatterjee,

Ghosh,

Datey

et al. 2023

J Virol

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Viruses use various strategies to modulate host pathways and take benefit of host machineries for efficient infection. It has been reported that certain viruses manipulate the Wnt/β-catenin pathway; however, its role in Chikungunya virus (CHIKV) infection has not yet been investigated. Hence, the focus of the current study was to evaluate the importance of the Wnt/β-catenin pathway in CHIKV infection using in vitro , in vivo , and ex vivo models. The study revealed that CHIKV infection suppressed the active β-catenin protein associated with Wnt/β-catenin signaling, which, in turn, led to the reduction of cyclin-D1 and upregulation of glycogen synthase kinase-3β. Inhibition of β-catenin by an inhibitor (iCRT14) showed a drastic reduction in the viral RNA, protein, and new viral particle formation in vitro . Next, it was found that β-catenin is important in different phases of viral life cycle. Notably, the treatment of CHIKV-infected C57BL/6 mice with this drug reduced the disease score substantially with a 91.7% decrease in the viral load. Similar result was observed in human peripheral blood mononuclear cell-derived monocyte-macrophage populations and in physiologically relevant cells like RAW264.7 and C2C12 cells. Additionally, knockdown of β-catenin by siRNA drastically reduced viral particle formation. Further investigation revealed that CHIKV-nsP2 interacts with β-catenin during CHIKV infection. In conclusion, this work demonstrated for the first time the mechanistic insights regarding the role of the Wnt/β-catenin pathway for CHIKV infection that might contribute to the designing of effective therapeutics for the control of this virus infection in future. IMPORTANCE Being obligate parasites, viruses use various host cell machineries in effectively replicating their genome, along with virus-encoded enzymes. In order to carry out infection and pathogenesis, viruses are known to manipulate fundamental cellular processes in cells and interfere with host gene expression. Several viruses interact with the cellular proteins involved in the Wnt/β-catenin pathway; however, reports regarding the involvement of protein components of the Wnt/β-catenin pathway in Chikungunya virus (CHIKV) infection are scarce. Additionally, there are currently no remedies or vaccines available for CHIKV. This is the first study to report that modulation of the Wnt/β-catenin pathway is crucial for effective CHIKV infection. These investigations deepen the understanding of the underlying mechanisms of CHIKV infection and offer new avenue for developing effective countermeasures to efficiently manage CHIKV infection.

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Section: Discussionmentioning

confidence: 99%

Chikungunya virus perturbs the Wnt/β-catenin signaling pathway for efficient viral infection

Chatterjee,

Ghosh,

Datey

et al. 2023

J Virol

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“…The resulting DNA lesions, particularly DNA double-strand breaks (DSBs), tend to induce genomic instability and disease development [ 11 , 12 ]. As a nuclear replicating virus, BoHV-1 infection induces oxidative DNA damage in multiple cell cultures, such as bovine kidney cells (MDBK) and human A549 lung carcinoma epithelial cells, as demonstrated by the increased production of DSBs analyzed by comet assay [ 10 , 13 , 14 ]. Accumulating studies have indicated that damaged DNA can activate various cell death pathways [ 13 ], and BoHV-1infection induces diverse forms of cell death both in vivo and in vitro [ 14 , 15 , 16 , 17 , 18 , 19 ], which underscores the implication of virus-infection-induced DNA damage in the virus pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…As a nuclear replicating virus, BoHV-1 infection induces oxidative DNA damage in multiple cell cultures, such as bovine kidney cells (MDBK) and human A549 lung carcinoma epithelial cells, as demonstrated by the increased production of DSBs analyzed by comet assay [ 10 , 13 , 14 ]. Accumulating studies have indicated that damaged DNA can activate various cell death pathways [ 13 ], and BoHV-1infection induces diverse forms of cell death both in vivo and in vitro [ 14 , 15 , 16 , 17 , 18 , 19 ], which underscores the implication of virus-infection-induced DNA damage in the virus pathogenesis. In addition, as an oncolytic virus, BoHV-1 infection in human lung adenocarcinoma cells A549 results in cell lesions partially by inducing DNA damage [ 10 ], which underlies the importance of DNA damage in the virus oncolytic effects.…”

Section: Introductionmentioning

confidence: 99%

DNA Damage Response Differentially Affects BoHV-1 Gene Transcription in Cell Type-Dependent Manners

Tang

Yuan

et al. 2022

Biomedicines

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Bovine herpesvirus 1 (BoHV-1), an important pathogen of cattle, is also a promising oncolytic virus. Recent studies have demonstrated that the virus infection induces DNA damage and DNA damage response (DDR), potentially accounting for virus infection-induced cell death and oncolytic effects. However, whether the global DDR network affects BoHV-1 productive infection remains to be elucidated. In this study, we show that global DDR induced by ultraviolet (UV) irradiation prior to BoHV-1 infection differentially affected transcription of immediate early (IE) genes, such as infected cell protein 0 (bICP0) and bICP22, in a cell-type-dependent manner. In addition, UV-induced DDR may affect the stabilization of viral protein levels, such as glycoprotein C (gC) and gD, because the variation in mRNA levels of gC and gD as a consequence of UV treatment were not in line with the variation in individual protein levels. The virus productive infection also affects UV-primed DDR signaling, as demonstrated by the alteration of phosphorylated histone H2AX (γH2AX) protein levels and γH2AX formation following virus infection. Taken together, for the first time, we evidenced the interplay between UV-primed global DDR and BoHV-1 productive infection. UV-primed global DDR differentially modulates the transcription of virus genes and stabilization of virus protein. Vice versa, the virus infection may affect UV-primed DDR signaling.

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53BP1, a known chromatin-associated factor that promotes DNA damage repair, is differentially modulated during bovine herpesvirus 1 infection in vitro and in vivo

Zhao,

Fu,

et al. 2025

Veterinary Microbiology

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β-Catenin-Specific Inhibitor, iCRT14, Promotes BoHV-1 Infection-Induced DNA Damage in Human A549 Lung Adenocarcinoma Cells by Enhancing Viral Protein Expression

Cited by 4 publications

References 33 publications

Chikungunya virus perturbs the Wnt/β-catenin signaling pathway for efficient viral infection

Chikungunya virus perturbs the Wnt/β-catenin signaling pathway for efficient viral infection

DNA Damage Response Differentially Affects BoHV-1 Gene Transcription in Cell Type-Dependent Manners

53BP1, a known chromatin-associated factor that promotes DNA damage repair, is differentially modulated during bovine herpesvirus 1 infection in vitro and in vivo

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