Key Takeaways & Executive Findings
- •• CSTF2 expression is upregulated in immune-reactive and inactive carrier phases of chronic HBV infection, correlating with reduced viral replication. • Overexpression of CSTF2 attenuates HBV DNA and protein levels without affecting HBV RNA levels, indicating a post-transcriptional regulatory mechanism. • CSTF2 relocalizes to the cytoplasm upon HBV transfection and interacts with the HBV PRE, impeding nuclear export of HBV RNA. • Distinct functional domains of CSTF2 exhibit varying antiviral efficacies, highlighting a multifaceted host defense mechanism and potential therapeutic target.
Abstract
The persistent global burden of hepatitis B virus (HBV) infection has prompted ongoing investigations into host determinants of viral control. In this study, we investigate the regulatory influence of the host gene cleavage stimulation factor subunit 2 (CSTF2) on HBV replication dynamics. We demonstrate differential CSTF2 expression across the spectrum of HBV infection phases, with upregulated expression noted during the immune-reactive and inactive carrier states compared with the immune-tolerant phase. Notably, dose-responsive attenuation of HBV DNA, as well as surface and core protein levels, is observed subsequent to CSTF2 overexpression, whereas HBV RNA levels remain unaffected. Upon HBV transfection, a notable alteration in CSTF2 subcellular localization is discerned, suggesting active relocalization to the cytoplasm, potentially mediated through interaction with the HBV posttranscriptional regulatory element (PRE). This interaction appears to impede the nuclear export of HBV RNA. Additionally, distinct antiviral efficacies are attributed to the functional domains of the CSTF2 protein, indicating a multifaceted host defense mechanism. These insights increase the understanding of host-virus interplay and identify CSTF2 as a candidate for antiviral therapeutic strategies.
1. Introduction
Hepatitis B virus (HBV) infection is a substantial public health challenge that contributes to considerable morbidity and mortality worldwide [1]. The natural history of chronic HBV infection is categorized into four distinct phases: immune-tolerant (IT), immune-reactive (IR), inactive carrier (IC), and HBeAg-negative active chronic hepatitis (ENH). Despite the apparent immunological quiescence shared by the IT and IC phases in chronic hepatitis B (CHB), these phases are characterized by divergent virological profiles. In the IT phase, individuals typically exhibit elevated viral loads exceeding 10^7 IU/mL, whereas the IC phase is associated with markedly lower viral loads, often below 2000 IU/mL. These observations implicate the role of immune-independent mechanisms in viral containment during phases of immunological dormancy.
In a previous investigation, we reported a significant elevation in intrahepatic mRNA level of the host gene cleavage stimulation factor subunit 2 (CSTF2) during the IC phase relative to the IT phase [2]. An inverse correlation was observed between CSTF2 expression and HBV replication, where CSTF2 downregulation was conducive to increased viral proliferation. CSTF2 forms an integral part of the cleavage stimulation factor (CSTF) complex, harboring an RNA recognition motif (RRM) essential for the precise processing of pre-mRNA [3]. The role of CSTF2 extends beyond that of HBV, with antecedent studies implicating its involvement in the modulation of human cytomegalovirus (HCMV) [4,5], human papillomavirus (HPV) [6,7], and enterovirus 71 (EV71) [8,9] infections, underscoring its broader impact on viral pathogenesis.
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Jinyu Wang, Jing Li, Wentao Xie, Zhongliang Shen, Jingwen Wu, Richeng Mao, Mengji Lu, Jiming Zhang (2026). The host gene CSTF2 regulates HBV replication via HBV PRE-induced nuclear export. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024216
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Frequently Asked Questions
What is the role of CSTF2 in HBV replication?
CSTF2 regulates HBV replication by interacting with the HBV posttranscriptional regulatory element (PRE) and impeding the nuclear export of HBV RNA, thereby reducing viral DNA and protein levels.
How does CSTF2 expression vary across HBV infection phases?
CSTF2 expression is upregulated in immune-reactive and inactive carrier phases compared to the immune-tolerant phase, correlating with lower viral loads.
Does CSTF2 affect HBV RNA levels?
No, CSTF2 overexpression does not affect HBV RNA levels, indicating a post-transcriptional mechanism of action.
What is the clinical significance of CSTF2?
CSTF2 is identified as a potential candidate for antiviral therapeutic strategies against HBV, offering a novel host-directed approach.
What are the functional domains of CSTF2?
The study attributes distinct antiviral efficacies to different functional domains of the CSTF2 protein, suggesting a multifaceted host defense mechanism.
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