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Research ArticleHepatologyVirology
Open Access | 
10.1172/JCI171533
1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
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1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
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1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
Find articles by Ren, L. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
Find articles by Wang, H. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
Find articles by Wang, X. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
Find articles by Zhu, W. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
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1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
Find articles by Li, Z. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
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1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
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1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
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Han, J.
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1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
Find articles by Kong, D. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
Find articles by Ji, J. in: JCI | PubMed | Google Scholar
1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
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1Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China.
2Department of Immunology, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
3Department of Pediatric Surgery, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
6MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
7Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Address correspondence to: Cong Liu, West China Second University Hospital, Sichuan University, Ren Ming Nan Lu, No. 17, Chengdu 610041, China. Phone: 0086.28.85501715; Email: congliu@scu.edu.cn. Or to: Antony M. Carr, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, BN1 9RQ, United Kingdom. Phone: 0044.1273.678122; Email: carr.am@sussex.ac.uk. Or to: Jianguo Ji, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.10.62755470; Email: jijg@pku.edu.cn. Or to: Daochun Kong, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Yiheyuan Lu No. 5, Haidian District, Beijing 100871, China. Phone: 0086.62760866; Email: kongdc@pku.edu.cn. Or to: Junhong Han, State Key Laboratory of Biotherapy, West China Hospital, Ren Ming Nan Lu, No. 17, Sichuan University, Chengdu 610041, China. Phone: 0086.028.61528677; Email: hjunhong@scu.edu.cn.
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
Find articles by Liu, C. in: JCI | PubMed | Google Scholar
Authorship note: MZ, ZT, LR, and HW contributed equally to this work.
Published October 10, 2023 - More info
Published in Volume 133, Issue 23 on December 1, 2023
AbstractMany cancers harbor homologous recombination defects (HRDs). A HRD is a therapeutic target that is being successfully utilized in treatment of breast/ovarian cancer via synthetic lethality. However, canonical HRD caused by BRCAness mutations do not prevail in liver cancer. Here we report a subtype of HRD caused by the perturbation of a proteasome variant (CDW19S) in hepatitis B virus–bearing (HBV-bearing) cells. This amalgamate protein complex contained the 19S proteasome decorated with CRL4WDR70 ubiquitin ligase, and assembled at broken chromatin in a PSMD4Rpn10- and ATM-MDC1-RNF8–dependent manner. CDW19S promoted DNA end processing via segregated modules that promote nuclease activities of MRE11 and EXO1. Contrarily, a proteasomal component, ADRM1Rpn13, inhibited resection and was removed by CRL4WDR70-catalyzed ubiquitination upon commitment of extensive resection. HBx interfered with ADRM1Rpn13 degradation, leading to the imposition of ADRM1Rpn13-dependent resection barrier and consequent viral HRD subtype distinguishable from that caused by BRCA1 defect. Finally, we demonstrated that viral HRD in HBV-associated hepatocellular carcinoma can be exploited to restrict tumor progression. Our work clarifies the underlying mechanism of a virus-induced HRD subtype.
Graphical Abstract
Introduction
Long-term liver infection with hepatitis B virus (HBV) predisposes carriers to hepatocellular carcinoma (1). Therapy for late-stage HBV-associated hepatocellular carcinoma remains a major challenge, with poor therapy responses and low overall survival (2). HBV subverts the Cullin4-DDB1-RING (CRL4) ubiquitin ligase for viral purposes via the oncoprotein HBx (3). Among the CRL4 subcomplexes that subsequently show reduced function is CRL4WDR70, a regulator for homologous recombination and chromatin remodeling (4). In HBV+ cells, enrichment of homologous recombination (HR) factors including RPA, RAD51, and EXO1 at DNA double-strand breaks (DSBs) is compromised, correlated to reduced CRL4WDR70 activity and DNA end resection (5). However, the mechanistic role of CRL4WDR70 in DNA repair remains undetermined.
Misregulation of DSB repair compromises chromosomal stability (6) and is often characterized by altered usage of non-homologous end joining (NHEJ) and HR (7). DNA end processing by 5′-to-3′ resection governs HR commitment by generating RPA-coated single-stranded DNA (ssDNA) that subsequently loads RAD51 to form a filament that enables homology search (8). The cell cycle position and the chromatin context surrounding the DSB site influence ssDNA production (9, 10). DSBs occurring in G1 are repaired by NHEJ, while those occurring after replication are repaired by NHEJ and/or HR. The choice of pathway is regulated by the competitive occupancy of 53BP1 and BRCA1 at DNA breaks (11–13). A new therapeutic strategy, synthetic lethality (SL), has recently been introduced for cancer subtype–specific chemotherapy, and this was first exemplified by the treatment of homologous recombination defect (HRD) breast cancers carrying BRCA1/2 mutations (BRCAness) with PARP inhibitors (PARPis), including olaparib and talazoparib (14).
DNA repair is also regulated by the 19S regulatory particle (RP), a constituent of the 26S proteasome that degrades ubiquitin-tagged proteins. Distinct from the protease activity sequestered in 20S core particle (CP), the canonical 19S RP recognizes ubiquitinated targets and deubiquitinates and positions them for translocation and unfolding to allow degradation by the CP (15). The 19S RP is subdivided into a “base” that is constituted of 6 paralogous AAA+ ATPases (PSMC1–6) plus several non-ATPase proteins (PSMD1Rpn2, PSMD2Rpn1, and ADRM1Rpn13) and a “lid” containing PCI domain proteins (PSMD3, 6, 8, 11–13), MPN domain proteins (PSMD7Rpn8 and POH1Rpn11), plus the non-PCI/MPN domain subunits including DSS1 (also known as Rpn15 or Sem1) (16, 17). The base and lid are conformationally dynamic and together bind a further subunit, the ubiquitin receptor PSMD4Rpn10.
As introduced above, in addition to regulating proteolysis, the RP also performs non-proteolytic roles in the context of chromatin. This was originally identified from the recruitment of a subset of RP proteins to the GAL1-10 promoter, implying a direct role in RNA polymerase II transcription (18). In the context of DNA repair, the 19S has subsequently been shown to modulate the efficiency of both DSB and nucleotide excision repair (19–21). DSS1Sem1 and POH1Rpn11 locate at DSB sites and regulate repair activities of RAD52/Pol4 and 53BP1/RAP80, respectively (22–25). The number and diversity of 19S-associating proteins and functions have obscured the elucidation of its mechanism in chromatin biology, and a comprehensive model depicting its interplay with DNA repair machinery is lacking.
Here we provide evidence that CRL4WDR70 forms a specific complex with the break-associated 19S proteasome (subsequently referred to as CDW19S; CULLIN4A-DDB1-WDR70-19S) that favors HR via end processing. 19S RP controls both MRE11 and EXO1 nucleases, and CRL4WDR70 engages with an EXO1-specific module of RPs to catalyze the ubiquitination and degradation of ADMR1Rpn13, a 19S-associated ubiquitin receptor that we identify as a resection barrier factor. We show that HBx disintegrates CUL4A-DDB1 from CDW19S and leaves scaffold-free WDR70-19S on damaged DNA. As such, HBx retards the clearance of ADRM1Rpn13 from DNA breaks, whereby a special HRD subtype is produced distinct from that caused by BRCA1 deficiency. Similar to the addiction of BRCAness cells to PARP functions, the viral HRD sensitizes HBV+ cells to PARPi. These data uncover a viral HRD subtype resulting from failed clearance of resection inhibitors.
ResultsHBx induces HRD by perturbing the balanced choice of DSB repair. To assess the impacts of HBV/HBx on DSB repair, an I-SceI–induced DSB system was used to measure sister chromatid repair (HR), single-strand annealing (SSA), and NHEJ efficiencies (26). T43 hepatocytes, which harbor integrated HBV genomes (5), displayed a modest decrease in HR and SSA relative to the parental HBV-free L02 cells (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/JCI171533DS1). To establish whether this HBV-induced HR deficiency can be attributed, at least in part, to HBx ablating CRL4WDR70, we expressed HBx in HEK293T cells and in WDR70-knockout derivatives (Figure 1A). HBx biased repair away from HR/SSA and toward NHEJ as expected. WDR70 deletion did not affect the repair profile beyond that seen when HBx is expressed in 293T cells, consistent with an epistatic relationship.
Figure 1Interference with CRL4WDR70 by HBx induces a viral HRD. (A) Repair frequency of indicated pathways in WDR70-knockout or HBx-expressing cells relative to control cells (293T). **P <0.05 by 2-tailed t test. NS, no statistic significance. (B) Left: Example confocal images showing 53BP1 (red) and RPA32 (green) IRIF in HBx-expressing L02 cells 8 hours after IR. Soluble nuclear proteins were preextracted with 0.1% Triton X-100. Scale bar: 10 μm. Right: Pixel intensity (vertical) across the maximal central line of individual IRIFs. Precipitation of red line (53BP1) and rising of green line (RPA32) along the vertical axis indicate the central cavity. (C and D) ChIP assay depicting p-RPA32 chromatin loading at indicated distance from the DSB upon expression of gRNA (g1) targeting the PPP1R12C/p84 locus. WDR70-knockout or control 293T cells (C) and L02 c
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