β‐catenin regulates IRF3‐mediated innate immune signalling in colorectal cancer

Ding, Chengming; He, Jun; Zhao, Jun; Li, Junhua; Chen, Jie; Liao, Wenyan; Zeng, Yi Arial; Zhong, Jing; Wei, Chaoying; Zhang, Liming; Zhou, Mei; Jia, Zeming; Zhang, Yaoting; Li, Hui; Zhou, Youyou; Xiao, Xiaolong; Han, Dongyi; Li, Chong; Zhu, Zhu; Xia, Zanxian; Peng, Jian

doi:10.1111/cpr.12464

Cited by 16 publications

(12 citation statements)

References 41 publications

(80 reference statements)

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“…Interestingly, viral targeting of ␤-catenin transcription activity has been observed in the context of infections with H1N1 influenza virus, human cytomegalovirus, Venezuelan equine encephalitis virus, and human immunodeficiency virus type 1 (11,(30)(31)(32). However, Ding et al showed that ␤-catenin downregulated IRF3-mediated signaling in human CRC cells (33). The discrepancy might be explained by different posttranslational modifications of ␤-catenin induced by different Wnt stimulants, as well as the infection of different cell types with different viruses.…”

Section: Discussionmentioning

confidence: 99%

β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein

You

Lin

et al. 2020

J Virol

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The cGAS/STING-mediated DNA-sensing signaling pathway is crucial for interferon (IFN) production and host antiviral responses. Herpes simplex virus I (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. Here, we demonstrate that the highly conserved β-catenin protein in the Wnt signaling pathway is an important factor to enhance the transcription of type I interferon (IFN-I) in the cGAS/STING signaling pathway, and the production of IFN-I mediated by β-catenin was antagonized by HSV-1 US3 protein via its kinase activity. Infection by US3-deficienct HSV-1 and its kinase-dead variants failed to downregulate IFN-I and IFN-stimulated gene (ISG) production induced by β-catenin. Consistent with this, absence of β-catenin enhanced the replication of US3-deficienct HSV-1, but not wild-type HSV-1. The underlying mechanism was the interaction of US3 with β-catenin and its hyperphosphorylation of β-catenin at Thr556 to block its nuclear translocation. For the first time, HSV-1 US3 has been shown to inhibit IFN-I production through hyperphosphorylation of β-catenin and to subvert host antiviral innate immunity. IMPORTANCE Although increasing evidence has demonstrated that HSV-1 subverts host immune responses and establishes lifelong latent infection, the molecular mechanisms by which HSV-1 interrupts antiviral innate immunity, especially the cGAS/STING-mediated cellular DNA-sensing signaling pathway, have not been fully explored. Here, we show that β-catenin promotes cGAS/STING-mediated activation of the IFN pathway, which is important for cellular innate immune responses and intrinsic resistance to DNA virus infection. The protein kinase US3 antagonizes the production of IFN by targeting β-catenin via its kinase activity. The findings in this study reveal a novel mechanism for HSV-1 to evade host antiviral immunity and add new knowledge to help in understanding the interaction between the host and HSV-1 infection.

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Section: Discussionmentioning

confidence: 99%

β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein

You

Lin

et al. 2020

J Virol

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“…It would be unlikely that this is the form present in the holocomplex formed by IRF3 and CBP/p300 described above. We and others have observed that when this form accumulates in response to the use of GSK-3 inhibitors, in the presence of Wnt ligands, or through β-catenin overexpression, it negatively affects the type I IFN response in cells following RLR stimulation [88][89][90]. However, other groups have reported the opposite in response to RNA viruses, including influenza A virus, human immunodeficiency virus (HIV), bovine parainfluenza virus type 3, and Rift Valley fever virus [40,81,82,91,92].…”

Section: Cytosolic Rna Sensorsmentioning

confidence: 99%

Roles of GSK-3 and β-Catenin in Antiviral Innate Immune Sensing of Nucleic Acids

Marineau

Khan

Servant

2020

Cells

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The rapid activation of the type I interferon (IFN) antiviral innate immune response relies on ubiquitously expressed RNA and DNA sensors. Once engaged, these nucleotide-sensing receptors use distinct signaling modules for the rapid and robust activation of mitogen-activated protein kinases (MAPKs), the IκB kinase (IKK) complex, and the IKK-related kinases IKKε and TANK-binding kinase 1 (TBK1), leading to the subsequent activation of the activator protein 1 (AP1), nuclear factor-kappa B (NF-κB), and IFN regulatory factor 3 (IRF3) transcription factors, respectively. They, in turn, induce immunomodulatory genes, allowing for a rapid antiviral cellular response. Unlike the MAPKs, the IKK complex and the IKK-related kinases, ubiquitously expressed glycogen synthase kinase 3 (GSK-3) α and β isoforms are active in unstimulated resting cells and are involved in the constitutive turnover of β-catenin, a transcriptional coactivator involved in cell proliferation, differentiation, and lineage commitment. Interestingly, studies have demonstrated the regulatory roles of both GSK-3 and β-catenin in type I IFN antiviral innate immune response, particularly affecting the activation of IRF3. In this review, we summarize current knowledge on the mechanisms by which GSK-3 and β-catenin control the antiviral innate immune response to RNA and DNA virus infections.

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“…IRF3 is part of the innate immune system, whose one of its major roles is to recognize and destroy infected and tumorous cells. Invivo and expression studies have implicated IRF3 in melanoma [36,37] and other cancer types [38,39].…”

Section: Single-gene Loci With Direct Interpretationmentioning

confidence: 99%

Recessive effects in cancer predisposition exposed by genome-wide and proteome-wide association studies

Brandes

Linial

2020

Preprint

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The characterization of germline genetic variation affecting cancer risk, known as cancer predisposition, is fundamental to preventive and personalized medicine. Current attempts to detect cancer predisposition genomic regions are typically based on small-scale familial studies or genome-wide association studies (GWAS) over dedicated case-control cohorts. In this study, we utilized the UK Biobank as a large-scale prospective cohort to conduct a comprehensive analysis of cancer predisposition using both GWAS and proteome-wide association study (PWAS), a method that highlights genetic associations mediated by functional alterations to protein-coding genes. We discovered 137 unique genomic loci implicated with cancer risk in the white British population across nine cancer types and pan-cancer. While most of these genomic regions are supported by external evidence, our results highlight novel loci as well. We performed a comparative analysis of cancer predisposition between cancer types, finding that most of the implicated regions are cancer-type specific. We further analyzed the role of recessive genetic effects in cancer predisposition. We found that 30 of the 137 cancer regions were recovered only by a recessive model, highlighting the importance of recessive inheritance outside of familial studies. Finally, we show that many of the cancer associations exert substantial cancer risk in the studied cohort, suggesting their clinical relevance.

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β‐catenin regulates IRF3‐mediated innate immune signalling in colorectal cancer

Abstract: Our study reveals an unprecedented role of β-catenin in enabling innate immune evasion in CRC.

Cited by 16 publications

References 41 publications

β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein

β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein

Roles of GSK-3 and β-Catenin in Antiviral Innate Immune Sensing of Nucleic Acids

Recessive effects in cancer predisposition exposed by genome-wide and proteome-wide association studies

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