Mutant p53 leads to low-grade IFN-I-induced inflammation and impairs cGAS-STING signalling in mice
© 2023 Wiley-VCH GmbH..
Type I interferons (IFN-Is) are a class of proinflammatory cytokines produced in response to viruses and environmental stimulations, resulting in chronic inflammation and even carcinogenesis. However, the connection between IFN-I and p53 mutation is poorly understood. Here, we investigated IFN-I status in the context of mutant p53 (p53N236S , p53S). We observed significant cytosolic double-stranded DNA (dsDNA) derived from nuclear heterochromatin in p53S cells, along with an increased expression of IFN-stimulated genes. Further study revealed that p53S promoted cyclic GMP-AMP synthase (cGAS) and IFN-regulatory factor 9 (IRF9) expression, thus activating the IFN-I pathway. However, p53S/S mice were more susceptible to herpes simplex virus 1 infection, and the cGAS-stimulator of IFN genes (STING) pathway showed a decline trend in p53S cells in response to poly(dA:dT) accompanied with decreased IFN-β and IFN-stimulated genes, whereas the IRF9 increased in response to IFN-β stimulation. Our results illustrated the p53S mutation leads to low-grade IFN-I-induced inflammation via consistent low activation of the cGAS-STING-IFN-I axis, and STAT1-IRF9 pathway, therefore, impairs the protective cGAS-STING signalling and IFN-I response encountered with exogenous DNA attack. These results suggested the dual molecular mechanisms of p53S mutation in inflammation regulation. Our results could be helping in further understanding of mutant p53 function in chronic inflammation and provide information for developing new therapeutic strategies for chronic inflammatory diseases or cancer.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2023 |
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Erschienen: |
2023 |
Enthalten in: |
Zur Gesamtaufnahme - volume:53 |
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Enthalten in: |
European journal of immunology - 53(2023), 9 vom: 26. Sept., Seite e2250211 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Qin, Ziyi [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 11.09.2023 Date Revised 11.09.2023 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.1002/eji.202250211 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM358785804 |
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520 | |a Type I interferons (IFN-Is) are a class of proinflammatory cytokines produced in response to viruses and environmental stimulations, resulting in chronic inflammation and even carcinogenesis. However, the connection between IFN-I and p53 mutation is poorly understood. Here, we investigated IFN-I status in the context of mutant p53 (p53N236S , p53S). We observed significant cytosolic double-stranded DNA (dsDNA) derived from nuclear heterochromatin in p53S cells, along with an increased expression of IFN-stimulated genes. Further study revealed that p53S promoted cyclic GMP-AMP synthase (cGAS) and IFN-regulatory factor 9 (IRF9) expression, thus activating the IFN-I pathway. However, p53S/S mice were more susceptible to herpes simplex virus 1 infection, and the cGAS-stimulator of IFN genes (STING) pathway showed a decline trend in p53S cells in response to poly(dA:dT) accompanied with decreased IFN-β and IFN-stimulated genes, whereas the IRF9 increased in response to IFN-β stimulation. Our results illustrated the p53S mutation leads to low-grade IFN-I-induced inflammation via consistent low activation of the cGAS-STING-IFN-I axis, and STAT1-IRF9 pathway, therefore, impairs the protective cGAS-STING signalling and IFN-I response encountered with exogenous DNA attack. These results suggested the dual molecular mechanisms of p53S mutation in inflammation regulation. Our results could be helping in further understanding of mutant p53 function in chronic inflammation and provide information for developing new therapeutic strategies for chronic inflammatory diseases or cancer | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a Chronic inflammation | |
650 | 4 | |a IFN-Is | |
650 | 4 | |a Innate immunity | |
650 | 4 | |a cGAS-STING pathway | |
650 | 4 | |a p53N236S mutation | |
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700 | 1 | |a Liu, Huan |e verfasserin |4 aut | |
700 | 1 | |a Sheng, Qihuan |e verfasserin |4 aut | |
700 | 1 | |a Dan, Juhua |e verfasserin |4 aut | |
700 | 1 | |a Wu, Xiaoming |e verfasserin |4 aut | |
700 | 1 | |a Li, Hao |e verfasserin |4 aut | |
700 | 1 | |a Wang, Lulin |e verfasserin |4 aut | |
700 | 1 | |a Zhang, Shuojie |e verfasserin |4 aut | |
700 | 1 | |a Yuan, Chao |e verfasserin |4 aut | |
700 | 1 | |a Yuan, Hongjun |e verfasserin |4 aut | |
700 | 1 | |a Wang, Hui |e verfasserin |4 aut | |
700 | 1 | |a Zhou, Ruoyu |e verfasserin |4 aut | |
700 | 1 | |a Luo, Ying |e verfasserin |4 aut | |
700 | 1 | |a Xie, Xiaoli |e verfasserin |4 aut | |
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