Apaf-1 is an evolutionarily conserved DNA sensor that switches the cell fate between apoptosis and inflammation
Abstract Apoptotic protease activating factor 1 (Apaf-1) was traditionally defined as a scaffold protein in mammalian cells for assembling a caspase activation platform known as the ‘apoptosome’ after its binding to cytochrome c. Although Apaf-1 structurally resembles animal NOD-like receptor (NLR)...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-024-00750-4 |
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| author | Jie Ruan Xuxia Wei Suizhi Li Zijian Ye Linyi Hu Ru Zhuang Yange Cao Shaozhou Wang Shengpeng Wu Dezhi Peng Shangwu Chen Shaochun Yuan Anlong Xu |
| author_facet | Jie Ruan Xuxia Wei Suizhi Li Zijian Ye Linyi Hu Ru Zhuang Yange Cao Shaozhou Wang Shengpeng Wu Dezhi Peng Shangwu Chen Shaochun Yuan Anlong Xu |
| author_sort | Jie Ruan |
| collection | DOAJ |
| description | Abstract Apoptotic protease activating factor 1 (Apaf-1) was traditionally defined as a scaffold protein in mammalian cells for assembling a caspase activation platform known as the ‘apoptosome’ after its binding to cytochrome c. Although Apaf-1 structurally resembles animal NOD-like receptor (NLR) and plant resistance (R) proteins, whether it is directly involved in innate immunity is still largely unknown. Here, we found that Apaf-1-like molecules from lancelets, fruit flies, mice, and humans have conserved DNA sensing functionality. Mechanistically, mammalian Apaf-1 recruits receptor-interacting protein 2 (RIP2, also known as RIPK2) via its WD40 repeat domain and promotes RIP2 oligomerization to initiate NF-κB-driven inflammation upon cytoplasmic DNA recognition. Furthermore, DNA binding of Apaf-1 determines cell fate by switching the cellular processes between intrinsic stimuli-activated apoptosis and inflammation. These findings suggest that Apaf-1 is an evolutionarily conserved DNA sensor and may serve as a cell fate checkpoint, which determines whether cells initiate inflammation or undergo apoptosis by distinct ligand binding. |
| format | Article |
| id | doaj-art-eb24f4a6a513487b826e5703f3b17d3b |
| institution | Kabale University |
| issn | 2056-5968 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj-art-eb24f4a6a513487b826e5703f3b17d3b2025-01-26T12:15:04ZengNature Publishing GroupCell Discovery2056-59682025-01-0111111810.1038/s41421-024-00750-4Apaf-1 is an evolutionarily conserved DNA sensor that switches the cell fate between apoptosis and inflammationJie Ruan0Xuxia Wei1Suizhi Li2Zijian Ye3Linyi Hu4Ru Zhuang5Yange Cao6Shaozhou Wang7Shengpeng Wu8Dezhi Peng9Shangwu Chen10Shaochun Yuan11Anlong Xu12Guangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, GuangzhouGuangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, GuangzhouGuangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, GuangzhouGuangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, GuangzhouGuangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, GuangzhouGuangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, GuangzhouGuangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, GuangzhouGuangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, GuangzhouGuangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, GuangzhouGuangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, GuangzhouGuangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, GuangzhouGuangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, GuangzhouGuangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, GuangzhouAbstract Apoptotic protease activating factor 1 (Apaf-1) was traditionally defined as a scaffold protein in mammalian cells for assembling a caspase activation platform known as the ‘apoptosome’ after its binding to cytochrome c. Although Apaf-1 structurally resembles animal NOD-like receptor (NLR) and plant resistance (R) proteins, whether it is directly involved in innate immunity is still largely unknown. Here, we found that Apaf-1-like molecules from lancelets, fruit flies, mice, and humans have conserved DNA sensing functionality. Mechanistically, mammalian Apaf-1 recruits receptor-interacting protein 2 (RIP2, also known as RIPK2) via its WD40 repeat domain and promotes RIP2 oligomerization to initiate NF-κB-driven inflammation upon cytoplasmic DNA recognition. Furthermore, DNA binding of Apaf-1 determines cell fate by switching the cellular processes between intrinsic stimuli-activated apoptosis and inflammation. These findings suggest that Apaf-1 is an evolutionarily conserved DNA sensor and may serve as a cell fate checkpoint, which determines whether cells initiate inflammation or undergo apoptosis by distinct ligand binding.https://doi.org/10.1038/s41421-024-00750-4 |
| spellingShingle | Jie Ruan Xuxia Wei Suizhi Li Zijian Ye Linyi Hu Ru Zhuang Yange Cao Shaozhou Wang Shengpeng Wu Dezhi Peng Shangwu Chen Shaochun Yuan Anlong Xu Apaf-1 is an evolutionarily conserved DNA sensor that switches the cell fate between apoptosis and inflammation Cell Discovery |
| title | Apaf-1 is an evolutionarily conserved DNA sensor that switches the cell fate between apoptosis and inflammation |
| title_full | Apaf-1 is an evolutionarily conserved DNA sensor that switches the cell fate between apoptosis and inflammation |
| title_fullStr | Apaf-1 is an evolutionarily conserved DNA sensor that switches the cell fate between apoptosis and inflammation |
| title_full_unstemmed | Apaf-1 is an evolutionarily conserved DNA sensor that switches the cell fate between apoptosis and inflammation |
| title_short | Apaf-1 is an evolutionarily conserved DNA sensor that switches the cell fate between apoptosis and inflammation |
| title_sort | apaf 1 is an evolutionarily conserved dna sensor that switches the cell fate between apoptosis and inflammation |
| url | https://doi.org/10.1038/s41421-024-00750-4 |
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