Keo-Heun Lim1, Eun-Sook Park1, Doo Hyun Kim1, Kyung Cho Cho2, Kwang Pyo Kim2, Yong Kwang Park1, Sung Hyun Ahn1, Seung Hwa Park3, Kee-Hwan Kim4, Chang Wook Kim5, Hong Seok Kang1, Ah Ram Lee1, Soree Park1, Heewoo Sim1, Juhee Won1, Kieun Seok1, Jueng Soo You6, Jeong-Hoon Lee7, Nam-Joon Yi8, Kwang-Woong Lee8, Kyung-Suk Suh8, Baik L Seong9, Kyun-Hwan Kim1,10,11. 1. Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea. 2. Department of Applied Chemistry, Kyung Hee University, Yongin, Gyeonggi, Korea. 3. Department of Anatomy, School of Medicine, Konkuk University, Seoul, Korea. 4. Department of Surgery, Uijeongbu St Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea. 5. Department of Internal Medicine, Uijeongbu St Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea. 6. Department of Biochemistry, School of Medicine, Konkuk University, Seoul, Korea. 7. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea. 8. Department of Surgery, Seoul National University College of Medicine, Seoul, Korea. 9. Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea. 10. KU Open Innovation Center, Konkuk University, Seoul, Korea. 11. Research Institute of Medical Sciences, Konkuk University, Seoul, Korea.
Abstract
OBJECTIVE: Interferons (IFNs) mediate direct antiviral activity. They play a crucial role in the early host immune response against viral infections. However, IFN therapy for HBV infection is less effective than for other viral infections. DESIGN: We explored the cellular targets of HBV in response to IFNs using proteome-wide screening. RESULTS: Using LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found several IFN-stimulated genes downregulated by HBx, including TRIM22, which is known as an antiretroviral protein. We demonstrated that HBx suppresses the transcription of TRIM22 through a single CpG methylation in its 5'-UTR, which further reduces the IFN regulatory factor-1 binding affinity, thereby suppressing the IFN-stimulated induction of TRIM22. CONCLUSIONS: We verified our findings using a mouse model, primary human hepatocytes and human liver tissues. Our data elucidate a mechanism by which HBV evades the host innate immune system. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
OBJECTIVE: Interferons (IFNs) mediate direct antiviral activity. They play a crucial role in the early host immune response against viral infections. However, IFN therapy for HBV infection is less effective than for other viral infections. DESIGN: We explored the cellular targets of HBV in response to IFNs using proteome-wide screening. RESULTS: Using LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found several IFN-stimulated genes downregulated by HBx, including TRIM22, which is known as an antiretroviral protein. We demonstrated that HBx suppresses the transcription of TRIM22 through a single CpG methylation in its 5'-UTR, which further reduces the IFN regulatory factor-1 binding affinity, thereby suppressing the IFN-stimulated induction of TRIM22. CONCLUSIONS: We verified our findings using a mouse model, primary human hepatocytes and human liver tissues. Our data elucidate a mechanism by which HBV evades the host innate immune system. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.