Dataset Information

SPI-2/CrmA inhibits IFN-? induction by targeting TBK1/IKK?.

ABSTRACT: Viruses modulate the host immune system to evade host antiviral responses. The poxvirus proteins serine proteinase inhibitor 2 (SPI-2) and cytokine response modifier A (CrmA) are involved in multiple poxvirus evasion strategies. SPI-2 and CrmA target caspase-1 to prevent apoptosis and cytokine activation. Here, we identified SPI-2 and CrmA as negative regulators of virus-triggered induction of IFN-?. Ectopic expression of SPI-2 or CrmA inhibited virus-triggered induction of IFN-? and its downstream genes. Consistently, knockdown of SPI-2 by RNAi potentiated VACV-induced transcription of antiviral genes. Further studies revealed that SPI-2 and CrmA associated with TBK1 and IKK? to disrupt the MITA-TBK1/IKK?-IRF3 complex. These findings reveal a novel mechanism of SPI-2/CrmA-mediated poxvirus immune evasion.

SUBMITTER: Qin Y

PROVIDER: S-EPMC5585206 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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SPI-2/CrmA inhibits IFN-β induction by targeting TBK1/IKKε.

Qin Yue Y Li Mi M Zhou Sheng-Long SL Yin Wei W Bian Zhuan Z Shu Hong-Bing HB

Scientific reports 20170905 1

Viruses modulate the host immune system to evade host antiviral responses. The poxvirus proteins serine proteinase inhibitor 2 (SPI-2) and cytokine response modifier A (CrmA) are involved in multiple poxvirus evasion strategies. SPI-2 and CrmA target caspase-1 to prevent apoptosis and cytokine activation. Here, we identified SPI-2 and CrmA as negative regulators of virus-triggered induction of IFN-β. Ectopic expression of SPI-2 or CrmA inhibited virus-triggered induction of IFN-β and its downstr ...[more]

PMID: 28874755

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Project description:Tumor metastasis is the major cause of death for prostate cancer (PCa) patients. However, the treatment options for metastatic PCa are very limited. Epithelial-mesenchymal transition (EMT) has been reported to be an indispensable step for tumor metastasis and is suggested to associate with acquisition of cancer stem cell (CSC) attributes. We propose that small-molecule compounds that can reverse EMT or induce mesenchymal-epithelial transition (MET) of PCa cells may serve as drug candidates for anti-metastasis therapy. Methods: The promoters of CDH1 and VIM genes were sub-cloned to drive the expression of firefly and renilla luciferase reporter in a lentiviral vector. Mesenchymal-like PCa cells were infected with the luciferase reporter lentivirus and subjected to drug screening from a 1274 approved small-molecule drug library for the identification of agents to reverse EMT. The dosage-dependent effect of candidate compounds was confirmed by luciferase reporter assay and immunoblotting. Wound-healing assay, sphere formation, transwell migration assay, and in vivo intracardiac and orthotopic tumor xenograft experiments were used to evaluate the mobility, metastasis and tumor initiating capacity of PCa cells upon treatment. Possible downstream signaling pathways affected by the candidate compound treatment were analyzed by RNA sequencing and immunoblotting. Results: Drug screening identified Amlexanox, a drug used for recurrent aphthous ulcers, as a strong agent to reverse EMT. Amlexanox induced significant suppression of cell mobility, invasion, serial sphere formation and in vivo metastasis and tumor initiating capacity of PCa cells. Amlexanox treatment led to downregulation of the IKK-?/ TBK1/ NF-?B signaling pathway. The effect of Amlexanox on EMT reversion and cell mobility inhibition can be mimicked by other IKK-?/TBK1 inhibitors and rescued by reconstitution of dominant active NF-?B. Conclusions: Amlexanox can sufficiently suppress PCa metastasis by reversing EMT through downregulating the IKK-?/TBK1/NF-?B signaling axis.

Dataset Information

SPI-2/CrmA inhibits IFN-? induction by targeting TBK1/IKK?.

Publications

SPI-2/CrmA inhibits IFN-β induction by targeting TBK1/IKKε.

Similar Datasets

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