The key role of structural cells in immune modulation has been revealed with the advent of single-cell multiomics,but the underlying mechanism remains poorly understood.Here,we revealed that the transcriptional activa...The key role of structural cells in immune modulation has been revealed with the advent of single-cell multiomics,but the underlying mechanism remains poorly understood.Here,we revealed that the transcriptional activation of interferon regulatory factor 1(IRF1)in response to ionizing radiation,cytotoxic chemicals and SARS-CoV-2 viral infection determines the fate of structural cells and regulates communication between structural and immune cells.Radiation-induced leakage of mtDNA initiates the nuclear translocation of IRF1,enabling it to regulate the transcription of inflammation-and cell death-related genes.Novel posttranslational modification(PTM)sites in the nuclear localization sequence(NLS)of IRF1 were identified.Functional analysis revealed that mutation of the acetylation site and the phosphorylation sites in the NLS blocked the transcriptional activation of IRF1 and reduced cell death in response to ionizing radiation.Mechanistically,reciprocal regulation between the single-stranded DNA sensors SSBP1 and IRF1,which restrains radiation-induced and STING/p300-mediated PTMs of IRF1,was revealed.In addition,genetic deletion or pharmacological inhibition of IRF1 tempered radiation-induced inflammatory cell death,and radiation mitigators also suppressed SARS-CoV-2 NSP-10-mediated activation of IRF1.Thus,we revealed a novel cytoplasm-oriented mechanism of IRF1 activation in structural cells that promotes inflammation and highlighted the potential effectiveness of IRF1 inhibitors against immune disorders.展开更多
[Objectives]This study was conducted to investigate the effect of interferon regulatory factor on the invasion and migration of tongue squamous carcinoma cells. [Methods]The expression level of IRF1 in tongue squamous...[Objectives]This study was conducted to investigate the effect of interferon regulatory factor on the invasion and migration of tongue squamous carcinoma cells. [Methods]The expression level of IRF1 in tongue squamous carcinoma tissues was detected by real-time quantitative PCR and immunohistochemistry. Plasmids for overexpression and knockdown of IRF1 were constructed. The effects of overexpression and knockdown of IRF1 on the proliferation, invasion and migration of Tca8113 cells were examined in Tca8113 cells. [Results] IRF1 expression was abnormally reduced in tongue squamous carcinoma tissues, and both real-time quantitative PCR and immunohistochemistry showed significantly lower expression than that of paraneoplastic controls. The overexpression and knockdown plasmids of IRF1 were successfully constructed. Growth curve assays showed that overexpression of IRF1 inhibited the proliferation of Tca8113 cells, while knockdown of IRF1 promoted the proliferation of Tca8113 cells. Scratch assay showed that overexpression of IRF1 inhibited the migration of Tca8113 cells, while knockdown of IRF1 promoted the migration of Tca8113 cells. Transwell assay showed that overexpression of IRF1 inhibited the invasion of Tca8113 cells, while knockdown of IRF1 promoted the invasion of Tca8113 cells. [Conclusions] In the development of tongue squamous carcinoma, IRF1 functions as an anti-oncogene, and the expression level of IRF1 was reduced in tongue squamous carcinoma tissues.展开更多
基金National Natural Science Foundation of China 82073477(SZ),32071238(DY)and 82203973(FG)Scientific Fund for Distinguished Young Scholars in Sichuan Province 2022JDJQ0051(SZ)and 2022NSFSC0797(CS)and Young Talent Project of China National Nuclear Corporation(SZ).
文摘The key role of structural cells in immune modulation has been revealed with the advent of single-cell multiomics,but the underlying mechanism remains poorly understood.Here,we revealed that the transcriptional activation of interferon regulatory factor 1(IRF1)in response to ionizing radiation,cytotoxic chemicals and SARS-CoV-2 viral infection determines the fate of structural cells and regulates communication between structural and immune cells.Radiation-induced leakage of mtDNA initiates the nuclear translocation of IRF1,enabling it to regulate the transcription of inflammation-and cell death-related genes.Novel posttranslational modification(PTM)sites in the nuclear localization sequence(NLS)of IRF1 were identified.Functional analysis revealed that mutation of the acetylation site and the phosphorylation sites in the NLS blocked the transcriptional activation of IRF1 and reduced cell death in response to ionizing radiation.Mechanistically,reciprocal regulation between the single-stranded DNA sensors SSBP1 and IRF1,which restrains radiation-induced and STING/p300-mediated PTMs of IRF1,was revealed.In addition,genetic deletion or pharmacological inhibition of IRF1 tempered radiation-induced inflammatory cell death,and radiation mitigators also suppressed SARS-CoV-2 NSP-10-mediated activation of IRF1.Thus,we revealed a novel cytoplasm-oriented mechanism of IRF1 activation in structural cells that promotes inflammation and highlighted the potential effectiveness of IRF1 inhibitors against immune disorders.
基金Supported by General Project of Hebei Provincial Department of Education Project (QN2019079)。
文摘[Objectives]This study was conducted to investigate the effect of interferon regulatory factor on the invasion and migration of tongue squamous carcinoma cells. [Methods]The expression level of IRF1 in tongue squamous carcinoma tissues was detected by real-time quantitative PCR and immunohistochemistry. Plasmids for overexpression and knockdown of IRF1 were constructed. The effects of overexpression and knockdown of IRF1 on the proliferation, invasion and migration of Tca8113 cells were examined in Tca8113 cells. [Results] IRF1 expression was abnormally reduced in tongue squamous carcinoma tissues, and both real-time quantitative PCR and immunohistochemistry showed significantly lower expression than that of paraneoplastic controls. The overexpression and knockdown plasmids of IRF1 were successfully constructed. Growth curve assays showed that overexpression of IRF1 inhibited the proliferation of Tca8113 cells, while knockdown of IRF1 promoted the proliferation of Tca8113 cells. Scratch assay showed that overexpression of IRF1 inhibited the migration of Tca8113 cells, while knockdown of IRF1 promoted the migration of Tca8113 cells. Transwell assay showed that overexpression of IRF1 inhibited the invasion of Tca8113 cells, while knockdown of IRF1 promoted the invasion of Tca8113 cells. [Conclusions] In the development of tongue squamous carcinoma, IRF1 functions as an anti-oncogene, and the expression level of IRF1 was reduced in tongue squamous carcinoma tissues.
