ADAR1 stimulation by IFN-α downregulates the expression of MAVS via RNA editing to regulate the anti-HBV response
Tao Li 1 , Xiaoshuang Yang 1 , Wei Li 2 , Jiaru Song 1 , Zhuo Li 3 , Xilin Zhu 1 , Xiaopan Wu 4 , Ying Liu 5
Affiliations
Affiliations
1
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College. Beijing, 100005, P. R. China.
2
Department of Interventional Radiology, the Affiliated Hospital of Qingdao University, Shandong 266003, China.
3
Department of Infectious Disease, Affiliated You'an Hospital, Capital University of Medical Science, Beijing 100069, China.
4
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College. Beijing, 100005, P. R. China. Electronic address: [email protected].
5
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College. Beijing, 100005, P. R. China. Electronic address: [email protected].
PMID: 33279720 DOI: 10.1016/j.ymthe.2020.11.031
Abstract
The partial response of CHB patients to IFN-α therapy remains elusive, which requires a better understanding of the involved molecular mechanism. In our study, bioinformatics analysis was applied to relate IFN-α regulated candidate genes and RNA editing sites by RNA sequencing. MAVS antiviral effect was confirmed in HepG2.2.15 cells and in two mouse models. The associations between polymorphisms in MAVS gene and response to IFN-α therapy were confirmed in CHB patients. We found that IFN-α downregulates MAVS via RNA editing that was mediated by ADAR1. ADAR1 inhibited MAVS expression via a HuR-mediated post-transcriptional regulation. MAVS exerted an antiviral activity and reduced the level of HBV markers in vitro and in vivo. IFN-α antiviral effects were significantly enhanced by MAVS co-transfection. HBc interacted with SP1 to inhibit the promoter activity of MAVS that regulate its expression. CHB patients with a rs3746662A allele had higher MAVS expression, thus were more responsive to IFN-α treatment. In this work we demonstrated that the decrease of MAVS expression is mediated by the IFN-α -ADAR1 axis. This study also highlighted the potential for the clinical application of MAVS in combination with IFN-α for the treatment of HBV infection.
Keywords: RNA editing; adenosine deaminase acting on RNA; hepatitis B virus; mitochondrial antiviral signaling protein; polymorphism.