In a groundbreaking study published in npj Viruses, researchers have unveiled critical insights into the mechanisms regulating the internal ribosome entry site (IRES)-like element activity of genotype one hepatitis E virus (HEV). The investigation elucidates how viral proteins — specifically helicase and methyltransferase — actively enhance the functionality of the IRES-like element, shedding light on the intricate molecular dance that enables viral protein synthesis under conditions where host translation is compromised. This work not only deepens our understanding of HEV biology but also offers potential targets for therapeutic intervention against this globally prevalent pathogen.
Hepatitis E virus stands as a significant cause of acute viral hepatitis worldwide, often linked to waterborne outbreaks and zoonotic transmission. Despite its public health prominence, much remains to be understood regarding how HEV orchestrates its replication cycle, especially at the level of viral translation initiation. Typically, eukaryotic translation depends on a cap-dependent mechanism requiring the 5’ cap structure on mRNAs. However, many viruses, including HEV, utilize specialized RNA elements called internal ribosome entry sites to hijack the host’s translational machinery, allowing cap-independent initiation of viral protein synthesis. The exact interaction between HEV’s IRES-like element and its viral proteins has remained elusive—until now.
The study’s authors probed the role of HEV non-structural proteins, focusing on helicase and methyltransferase, in modulating the virus’s IRES-like element activity. Helicases are enzymes often implicated in unwinding RNA secondary structures, thereby facilitating ribosome scanning or assembly onto the target RNA. Methyltransferases, conversely, are known for modifying RNA or protein surfaces through methylation, which can influence RNA stability and interaction dynamics. By employing sophisticated molecular assays, the researchers demonstrated that both helicase and methyltransferase significantly boost the IRES-like element’s activity, enabling more effective ribosome recruitment and initiation of translation.
Their experiments revealed a synergistic effect: helicase’s RNA remodeling activity appears to expose or stabilize critical structural motifs within the IRES-like element, making it more accessible to the translational machinery. Meanwhile, methyltransferase-mediated modifications may modulate the RNA-protein interactions required for optimal translation initiation. This dual enhancement hints at a finely tuned viral strategy to maximize protein production even when host cap-dependent mechanisms are downregulated, such as during antiviral responses or cellular stress.
Interestingly, the findings suggest that the genotype one HEV IRES-like element is functionally analogous to well-characterized IRES elements from other viruses, yet exhibits unique regulatory features dictated by its interaction with viral enzymes. The study detailed how mutation or inhibition of either helicase or methyltransferase significantly reduced IRES-like activity, underscoring their essential roles. This dependency could be exploited pharmacologically: targeted inhibitors disrupting these interactions might suppress viral replication without affecting host cell translation.
The experimentation involved in this discovery combined biochemical assays, reporter gene analysis, and RNA structure probing. The team constructed various mutant viral RNA templates and expressed mutant proteins to dissect the individual contributions of helicase and methyltransferase domains. Their meticulous dissection of structure-function relationships illuminated how specific amino acid residues and RNA motifs contribute to the overall assembly and efficiency of the translation initiation complex on the IRES-like element.
Beyond advancing molecular virology, this research carries clinical implications. HEV infection is globally widespread, with certain genotypes causing chronic infections in immunocompromised individuals and severe disease in pregnant women. The robust translation mechanism highlighted by this study could partially explain the virus’s persistence and pathogenicity. Targeting helicase and methyltransferase functions offers a rational antiviral strategy, potentially leading to novel therapeutics that disrupt viral protein synthesis at its earliest stages.
Moreover, the study enriches the broader field of RNA biology by illustrating how viral enzymes can sculpt RNA landscapes to favor translation. Such examples underscore viruses’ evolutionary ingenuity in co-opting host machinery and overcoming cellular hurdles. The detailed mechanistic insights from genotype one HEV could also inform research into other viral pathogens employing IRES-dependent translation, revealing common vulnerabilities or divergent adaptations.
This work also prompts revisiting the role of viral non-structural proteins beyond their canonical enzymatic activities. The demonstration that helicase and methyltransferase serve dual functions—both enzymatic and regulatory—highlights a multifunctional aspect of viral proteins that warrant deeper exploration across diverse viral families. It suggests that viral replication complexes are highly integrated structures where enzymatic activity and RNA interaction converge to fine-tune infection processes.
From a methodological perspective, the combination of mutational analysis with advanced in vitro translation assays sets a new standard for studying complex RNA-protein interplay during virus-host interactions. The careful validation of IRES-like element activity through reporter constructs and the use of RNA footprinting techniques underscore the value of interdisciplinary approaches in virology research.
Future studies will be necessary to fully delineate how these viral proteins interact with host translation factors and how cellular stress responses may modulate the IRES-like element activity. Additionally, investigations into how genotype variations influence helicase and methyltransferase functions could reveal genotype-specific therapeutic windows or explain differences in disease outcomes across populations.
The discovery that viral helicase and methyltransferase collaboratively promote HEV’s internal ribosome entry site-like element marks a significant advancement in understanding viral translation strategies. By illuminating previously unappreciated molecular facilitators of genotype one HEV protein synthesis, the research opens promising avenues for antiviral development and deepens our grasp of virus-host molecular crosstalk.
As the scientific community continues to unravel the intricate mechanisms underpinning viral replication, studies like this emphasize the importance of considering multifunctional viral proteins and RNA regulatory elements as potent determinants of viral fitness and pathogenicity. The integration of molecular virology, structural biology, and translational research exemplified by this work charts a path forward in combating hepatitis E and related viral threats worldwide.
In summary, Kumar and colleagues have provided compelling evidence that the cooperative action of viral helicase and methyltransferase significantly enhances the internal ribosome entry site-like element activity in genotype one hepatitis E virus. This novel insight not only enriches the fundamental understanding of viral translation mechanisms but also offers a framework for targeted antiviral strategies against a pervasive human pathogen.
Subject of Research:
Enhancement of genotype one hepatitis E virus internal ribosome entry site-like element activity by viral helicase and methyltransferase proteins.
Article Title:
Viral helicase and methyltransferase promote genotype one-hepatitis E virus internal ribosome entry site-like element activity.
Article References:
Kumar, S., Mehta, S., Gupta, J. et al. Viral helicase and methyltransferase promote genotype one-hepatitis E virus internal ribosome entry site-like element activity. npj Viruses 3, 77 (2025). https://doi.org/10.1038/s44298-025-00159-0
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AI Generated
DOI:
https://doi.org/10.1038/s44298-025-00159-0
