RNA‐binding motif protein 24 inhibits HBV replication in vivo

Abstract

Despite the extensive use of effective vaccines and antiviral drugs, chronic hepatitis B virus (HBV) infection continues to pose a serious threat to global public health. Therapies with novel mechanisms of action against HBV are being explored for achieving a functional cure. In this study, five murine models of HBV replication were used to investigate the inhibitory effect of RNA binding motif protein 24 (RBM24) on HBV replication. The findings revealed that RBM24 serves as a host restriction factor and suppresses HBV replication in vivo. The transient overexpression of RBM24 in hydrodynamics‐based mouse models of HBV replication driven by the CMV or HBV promoters suppressed HBV replication. Additionally, the ectopic expression of RBM24 decreased viral accumulation and the levels of HBV covalently closed circular DNA (cccDNA) in an rcccDNA mouse model. The liver‐directed transduction of adeno‐associated viruses (AAV)‐RBM24 mediated the stable hepatic expression of RBM24 in pAAV‐HBV1.2 and HBV/tg mouse models, and markedly reduced the levels of HBV cccDNA and other viral indicators. Altogether, these findings revealed that RBM24 inhibits the replication of HBV in vivo, and RBM24 may be a potential therapeutic target for combating HBV infections.

Deciphering the phospho-signature induced by hepatitis B virus in primary human hepatocytes

“…In both cell types, we found that knock-down of HNRNPU or SRRM2 resulted in an increase of HBV RNAs, both total RNAs and pgRNA, without significantly affecting cccDNA levels, and in the absence of any visible cytotoxic effect ( Figures 5C , E ). These results indicate that, as previously reported for other cellular RBPs, these factors behave as anti-viral factors that exert their functions at a transcriptional and/or post-transcriptional level ( Sun et al, 2017 ; Yao et al, 2018 , 2019 ; Chabrolles et al, 2020 ; Yao Y. X. et al, 2023 ).…”

“…In the present study, several RBPs were up-phosphorylated upon HBV infection. The HBc protein itself, which has a positively-charged, intrinsically disordered C-terminal domain similar to that found in many cellular RBPs, can interact with a network of RBPs, some of which possess anti-viral activities ( Diab et al, 2018 ; Chabrolles et al, 2020 ; Yao Y. X. et al, 2023 ; Zhang et al, 2023 ). Many if not all RBPs are tightly regulated by their phosphorylation level which controls their intra-cellular and intra-nuclear localization, their capacity to form condensates by liquid–liquid phase separation, their interaction with other protein partners, as well their affinity for RNA and DNA ( Hofweber and Dormann, 2019 ; Velazquez-Cruz et al, 2021 ; He et al, 2023 ).…”