DNA Sensor ABCF1 Phase Separates With cccDNA to Inhibit Hepatitis B Virus Replication
Abstract Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) contributes to viral persistence and recurrence, however, how the host innate immune system responds to cccDNA is still less known. Here, based on cccDNA‐hepatic proteins interaction profiling, DNA sensor ATP‐binding cassette s...
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202409485 |
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| author | Caiyue Ren Zhaoying Zhang Yutong Dou Yang Sun Zhendong Fu Liyuan Wang Kai Wang Chengjiang Gao Yuchen Fan Shuguo Sun Xuetian Yue Chunyang Li Lifen Gao Xiaohong Liang Chunhong Ma Zhuanchang Wu |
| author_facet | Caiyue Ren Zhaoying Zhang Yutong Dou Yang Sun Zhendong Fu Liyuan Wang Kai Wang Chengjiang Gao Yuchen Fan Shuguo Sun Xuetian Yue Chunyang Li Lifen Gao Xiaohong Liang Chunhong Ma Zhuanchang Wu |
| author_sort | Caiyue Ren |
| collection | DOAJ |
| description | Abstract Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) contributes to viral persistence and recurrence, however, how the host innate immune system responds to cccDNA is still less known. Here, based on cccDNA‐hepatic proteins interaction profiling, DNA sensor ATP‐binding cassette subfamily F member 1 (ABCF1) is identified as a novel cccDNA‐binding protein and host restriction factor for HBV replication. Mechanistically, ABCF1 recognizes cccDNA by KKx4 motif and forms phase‐separated condensates by the poly‐glutamine (PolyQ) region of the N‐terminal intrinsically disordered low‐complexity domain (LCD). Subsequently, ABCF1‐cccDNA phase separation not only activates the type I/III interferon (IFN‐I/III) pathway but also prevents Pol II accumulation on cccDNA to inhibit HBV transcription. In turn, to sustain viral replication, HBV reduces ABCF1 expression by HBx‐mediated ubiquitination and degradation of SRY‐box transcription factor 4（SOX4）, leading to defects in SOX4‐mediated upregulation of ABCF1 transcription. Taken together, the study shows that ABCF1 interacts with cccDNA to form phase separation that dually drives innate immune signaling and HBV transcriptional inhibition. These findings shed new light on the understanding of host defense against cccDNA and provide a novel promising therapeutic strategy for HBV infection. |
| format | Article |
| id | doaj-art-fa3a44afe838477e8c2de0585dfbb6c0 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-fa3a44afe838477e8c2de0585dfbb6c02025-08-20T02:01:00ZengWileyAdvanced Science2198-38442024-12-011148n/an/a10.1002/advs.202409485DNA Sensor ABCF1 Phase Separates With cccDNA to Inhibit Hepatitis B Virus ReplicationCaiyue Ren0Zhaoying Zhang1Yutong Dou2Yang Sun3Zhendong Fu4Liyuan Wang5Kai Wang6Chengjiang Gao7Yuchen Fan8Shuguo Sun9Xuetian Yue10Chunyang Li11Lifen Gao12Xiaohong Liang13Chunhong Ma14Zhuanchang Wu15Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Cheeloo Medical College Shandong University Jinan Shandong 250012 ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Cheeloo Medical College Shandong University Jinan Shandong 250012 ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Cheeloo Medical College Shandong University Jinan Shandong 250012 ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Cheeloo Medical College Shandong University Jinan Shandong 250012 ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Cheeloo Medical College Shandong University Jinan Shandong 250012 ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Cheeloo Medical College Shandong University Jinan Shandong 250012 ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Cheeloo Medical College Shandong University Jinan Shandong 250012 ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Cheeloo Medical College Shandong University Jinan Shandong 250012 ChinaDepartment of Hepatology Qilu Hospital Cheeloo Medical College Shandong University Jinan Shandong 250012 ChinaDepartment of Human Anatomy, Histology and Embryology School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 ChinaDepartment of Cellular Biology School of Basic Medical Sciences Shandong University Jinan Shandong 250012 ChinaKey Laboratory for Experimental Teratology of the Ministry of Education Department of Histology and Embryology School of Basic Medical Sciences Shandong University Jinan Shandong 250012 ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Cheeloo Medical College Shandong University Jinan Shandong 250012 ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Cheeloo Medical College Shandong University Jinan Shandong 250012 ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Cheeloo Medical College Shandong University Jinan Shandong 250012 ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Cheeloo Medical College Shandong University Jinan Shandong 250012 ChinaAbstract Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) contributes to viral persistence and recurrence, however, how the host innate immune system responds to cccDNA is still less known. Here, based on cccDNA‐hepatic proteins interaction profiling, DNA sensor ATP‐binding cassette subfamily F member 1 (ABCF1) is identified as a novel cccDNA‐binding protein and host restriction factor for HBV replication. Mechanistically, ABCF1 recognizes cccDNA by KKx4 motif and forms phase‐separated condensates by the poly‐glutamine (PolyQ) region of the N‐terminal intrinsically disordered low‐complexity domain (LCD). Subsequently, ABCF1‐cccDNA phase separation not only activates the type I/III interferon (IFN‐I/III) pathway but also prevents Pol II accumulation on cccDNA to inhibit HBV transcription. In turn, to sustain viral replication, HBV reduces ABCF1 expression by HBx‐mediated ubiquitination and degradation of SRY‐box transcription factor 4（SOX4）, leading to defects in SOX4‐mediated upregulation of ABCF1 transcription. Taken together, the study shows that ABCF1 interacts with cccDNA to form phase separation that dually drives innate immune signaling and HBV transcriptional inhibition. These findings shed new light on the understanding of host defense against cccDNA and provide a novel promising therapeutic strategy for HBV infection.https://doi.org/10.1002/advs.202409485ABCF1cccDNAHBVHBxphase separationtranscriptional machinery |
| spellingShingle | Caiyue Ren Zhaoying Zhang Yutong Dou Yang Sun Zhendong Fu Liyuan Wang Kai Wang Chengjiang Gao Yuchen Fan Shuguo Sun Xuetian Yue Chunyang Li Lifen Gao Xiaohong Liang Chunhong Ma Zhuanchang Wu DNA Sensor ABCF1 Phase Separates With cccDNA to Inhibit Hepatitis B Virus Replication Advanced Science ABCF1 cccDNA HBV HBx phase separation transcriptional machinery |
| title | DNA Sensor ABCF1 Phase Separates With cccDNA to Inhibit Hepatitis B Virus Replication |
| title_full | DNA Sensor ABCF1 Phase Separates With cccDNA to Inhibit Hepatitis B Virus Replication |
| title_fullStr | DNA Sensor ABCF1 Phase Separates With cccDNA to Inhibit Hepatitis B Virus Replication |
| title_full_unstemmed | DNA Sensor ABCF1 Phase Separates With cccDNA to Inhibit Hepatitis B Virus Replication |
| title_short | DNA Sensor ABCF1 Phase Separates With cccDNA to Inhibit Hepatitis B Virus Replication |
| title_sort | dna sensor abcf1 phase separates with cccdna to inhibit hepatitis b virus replication |
| topic | ABCF1 cccDNA HBV HBx phase separation transcriptional machinery |
| url | https://doi.org/10.1002/advs.202409485 |
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