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The Post-Transcriptional Regulatory Element of Hepatitis B Virus: From Discovery to Therapy - PubMed

  • ️Mon Jan 01 2024

Review

The Post-Transcriptional Regulatory Element of Hepatitis B Virus: From Discovery to Therapy

Karim Mouzannar et al. Viruses. 2024.

Abstract

The post-transcriptional regulatory element (PRE) is present in all HBV mRNAs and plays a major role in their stability, nuclear export, and enhancement of viral gene expression. Understanding PRE's structure, function, and mode of action is essential to leverage its potential as a therapeutic target. A wide range of PRE-based reagents and tools have been developed and assessed in preclinical and clinical settings for therapeutic and biotechnology applications. This manuscript aims to provide a systematic review of the characteristics and mechanism of action of PRE, as well as elucidating its current applications in basic and clinical research. Finally, we discuss the promising opportunities that PRE may provide to antiviral development, viral biology, and potentially beyond.

Keywords: PRE; RNA; RNA tailing; TENT4A/B; ZCCHC14; hepatitis B; therapeutics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Schematic representation of HBV genome organization, transcripts, and PRE bipartite structure. (A) HBV genetic map. HBV rcDNA is depicted with its negative (orange) and discontinuous positive (purple) strands, DR1/DR2 intersection, and covalently attached HBV polymerase (P). The four overlapping open-reading frames (preC/C, P, PreS1/preS2/S, and X) are shown (green arrows). Four classes of transcripts generated by HBV that terminate at a shared polyadenylation site (polyA) are shown (black arrows). (B) HBV transcripts. The five HBV RNA transcripts are shown, each depicting the transcription start site (TSS) at the 5′ cap termini (black circles), and several viral cis-elements: PRE, polyadenylation stimulating sequence (PSS), unconventional UAUAAA poly(A) signal (PAS), and ZAP-responsive element (ZRE). Nucleotide numbering is based on HBV genotype D. (C) PRE bipartite structure. An expanded view of PRE shows that all HBV RNA transcripts contain a complete PRE, except for HBx mRNA. Complete PRE is composed of PREα and PREß (containing elements PREß1 and PREß2). PREα has a La protein binding site (La) and a conserved stem–loop structure (SLα). PREß1 has a stem–loop structure (SLß). PREß2 has a polypyrimidine binding protein 1 docking site (PTBP1). Figure was created with

Biorender.com

.

Figure 2
Figure 2

Schematic representation of PRE mode of action. (A) ZCCHC14 and TENT4A/B form a complex with the SLα pentaloop (CAGGU) of HPRE to initiate polyadenylation at the 3′ end, facilitating protection of HBV RNA against degradation, nuclear export to the cytoplasm, and translation. (B) RG7834 is a small molecule that specifically inhibits TENT4A/B enzymatic activity, thus blocking mixed tailing on the 3′ end of HBV RNA. This blockage leads to the degradation of HBV RNA by cellular nucleases, potently suppressing HBV replication both in vitro and in vivo. Figure created with

Biorender.com

.

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