Molecular mechanism of RBM15-mediated m6A modification in hepatitis B virus replication

作者: Min Ni, Bingbing Li, Lingli Wang, Shengju Ma, Kun Ma
杂志: Virology Journal
Doi: https://www.doi.org/10.1186/s12985-025-03008-x
出版日期: 2025/12/22

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摘要

Background
Hepatitis B virus (HBV) is a major human pathogen and chronically infects over 250 million people globally. The objective of our study is to investigate the mechanism of RBM15 in HBV replication, providing novel targets for HB treatment.

Methods
Huh-7 cells were treated with pHBV1.3. pHBV1.3 replication in Huh-7 cells was verified by detection of HBV RNAs, HBV pgRNA and HBx levels. The expression of RBM15, HULC and BRD4 was detected by qRT-PCR or WB. After RBM15 intervention, the effect of RBM15 on HBV replication was evaluated by detections of HBV DNA and HBV RNAs via q-PCR or qRT-PCR, HBsAg and HBeAg through ELISA. Total m6A levels were analyzed by m6A quantification. The m6A enrichment on HULC was analyzed by MeRIP. Bindings of HULC to ELAVL1, and ELAVL1 to BRD4 mRNA were examined by RIP. BRD4 stability was evaluated following actinomycin D treatment. HULC or BRD4 overexpression was combined with RBM15 inhibition to validate the mechanism. Finally, the HBV replication mouse model was established for mechanism verification.

Results
RBM15 was overexpressed during HBV replication. RBM15 inhibition suppressed HBV replication. RBM15 enhanced the m6A modification on HULC and stabilized HULC expression. HULC bound to ELAVL1 and elevated BRD4 protein expression. HULC or BRD4 overexpression partially reversed the inhibitory effect of RBM15 on HBV replication.

Conclusions
RBM15 enhances HBV replication by promoting the binding of HULC to ELAVL1 through m6A modification, and increasing BRD4 expression.

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