IRF3 activates RB to authorize cGAS-STING-induced senescence and mitigate liver fibrosis
Cytosolic double-stranded DNA surveillance by cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) signaling triggers cellular senescence, autophagy, biased mRNA translation, and interferon-mediated immune responses. However, detailed mechanisms and physiological relevance of STING-induced senescence are not fully understood. Here, we unexpectedly found that interferon regulatory factor 3 (IRF3), activated during innate DNA sensing, forms substantial endogenous complexes in the nucleus with retinoblastoma (RB), a key cell cycle regulator. The IRF3-RB interaction attenuates cyclin-dependent kinase 4/6 (CDK4/6)-mediated RB hyperphosphorylation that mobilizes RB to deactivate E2 family (E2F) transcription factors, thereby driving cells into senescence. STING-IRF3-RB signaling plays a notable role in hepatic stellate cells (HSCs) within various murine models, pushing activated HSCs toward senescence. Accordingly, IRF3 global knockout or conditional deletion in HSCs aggravated liver fibrosis, a process mitigated by the CDK4/6 inhibitor. These findings underscore a straightforward yet vital mechanism of cGAS-STING signaling in inducing cellular senescence and unveil its unexpected biology in limiting liver fibrosis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Science advances - 10(2024), 9 vom: 01. März, Seite eadj2102 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wu, Qirou [VerfasserIn] |
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| Links: |
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| Themen: |
9007-49-2 |
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| Anmerkungen: |
Date Completed 01.03.2024 Date Revised 01.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1126/sciadv.adj2102 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369067347 |
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| 520 | |a Cytosolic double-stranded DNA surveillance by cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) signaling triggers cellular senescence, autophagy, biased mRNA translation, and interferon-mediated immune responses. However, detailed mechanisms and physiological relevance of STING-induced senescence are not fully understood. Here, we unexpectedly found that interferon regulatory factor 3 (IRF3), activated during innate DNA sensing, forms substantial endogenous complexes in the nucleus with retinoblastoma (RB), a key cell cycle regulator. The IRF3-RB interaction attenuates cyclin-dependent kinase 4/6 (CDK4/6)-mediated RB hyperphosphorylation that mobilizes RB to deactivate E2 family (E2F) transcription factors, thereby driving cells into senescence. STING-IRF3-RB signaling plays a notable role in hepatic stellate cells (HSCs) within various murine models, pushing activated HSCs toward senescence. Accordingly, IRF3 global knockout or conditional deletion in HSCs aggravated liver fibrosis, a process mitigated by the CDK4/6 inhibitor. These findings underscore a straightforward yet vital mechanism of cGAS-STING signaling in inducing cellular senescence and unveil its unexpected biology in limiting liver fibrosis | ||
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| 700 | 1 | |a Leng, Xiaohong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Ye-Zhang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Ruyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yutong |e verfasserin |4 aut | |
| 700 | 1 | |a Mei, Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Shengduo |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Shasha |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiaojian |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Aifu |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Xia |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Tingbo |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Xin-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, Bing |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Pinglong |e verfasserin |4 aut | |
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