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In a nutshell
• Caught in action: A research team has revealed how the molecular copying machine of the influenza virus, termed FluPol, interacts with the human copying machinery inside the infected cell to steal the cap of the host RNA.
• Molecular mechanism decoded: Visualizing at atomic resolution this process of theft, commonly called cap-snatching, elucidates a key step in how one of the most common human viral pathogens reproduces.
• Activity of the viral copying machine can be influenced: Altering the parts in the viral copying machine that interact with the human copying machine, reduces FluPol activity in living cells and could therefore be a new target for antiviral drugs.
The cold season is in full swing, throats are scratchy and noses are running. We feel ill and hope it is not the flu. The influenza virus continues to pose a threat to our health. It triggers seasonal epidemics and, from time to time, potentially serious global pandemics. Existing antiviral drugs are often less effective than hoped because the influenza virus mutates rapidly to escape their effect. Accordingly, vaccines also must be adapted every year. However, influenza viruses have an “Achilles’ heel” that can be exploited for therapeutic purposes: the viral copying machine. Researchers from Göttingen, in collaboration with colleagues at research institutions in France, have now observed in molecular detail how the viral copying machine performs one of the key steps required for viral replication. They made visible how the influenza virus interacts with the host copying machine and steals the cap of the host RNA to use it for itself.
Molecular theft
Influenza viruses are RNA viruses with a genome consisting of single-stranded RNA. Like other viruses, the influenza virus smuggles its genetic material into the host cell and uses its host’s molecular repertoire to produce new virus particles. In doing so, the influenza virus effectively bypasses the protective measures of the host cell. By stealing the host RNA cap, the influenza virus not only promotes its own replication but also circumvents one of the host cell’s protective measures.
The molecular “copying machines” of the host cell and the virus, both known as polymerases, play a key role in this process. In the host cell, the human’s polymerase role is to first transcribe genomic DNA into pre-mRNA. The pre-mRNA, early in its synthesis, is marked with a chemical structure at its beginning, called the cap. The cap is absolutely required to enable mature mRNA to act as a blueprint to make proteins. But in addition, the cap marks the cell’s RNA as “self” and harmless. If the protective cap is missing, the immune system recognizes the RNA as foreign and potentially harmful RNA, triggering an antiviral response.
“Most viruses, have their own mechanisms to attach the cap, thereby hiding their mRNA from the host’s immune system. However, the influenza virus lacks this ability. Instead, its polymerase has evolved a unique cap-snatching mechanism. We have now succeeded in visualizing this process in molecular detail as part of an international collaboration,” says Patrick Cramer from the Max Planck Society and last author of the study now published in the scientific magazine Nature.
Cleverly disguised
What has been known for many years is that in order to mark its mRNAs with the all-important cap structure, the copying machine of the influenza virus, called FluPol, goes on a hunt, stealing the cap from the host RNA. The host cell then recognizes the viral mRNA as a template for protein production and begins to produce all the proteins necessary for viral replication. It is also already known that FluPol interacts with the host’s copying machinery during this theft. However, the detailed mechanism remained unclear.
“Exactly how cap-snatching works has been a puzzle in the influenza field for years,”, says Stephen Cusack from EMBL in Grenoble (France), a pioneer in structural analysis of FluPol. “It requires that FluPol hijacks the normal course of host RNA synthesis, diverting it for the benefit of the virus and to the detriment of the cell. To solve this puzzle, we joined forces with Patrick Cramer, a world leader in cellular polymerases.”
An interdisciplinary research team led by Patrick Cramer, Stephen Cusack and Nadia Naffakh at the Institut Pasteur located in Paris, have now revealed, for the first time, how cap-snatching takes place. In biochemical experiments, the research team managed to reconstitute the process in the test tube. They stopped the reaction at various steps and used cryo-electron microscopy to visualize the structures and interactions of the proteins involved in three dimensions and at near atomic resolution.
Theft in three stages
“We have discovered that cap-snatching can be divided into three main steps,” reports Alexander Rotsch, former doctoral student in the Department of Molecular Biology at the Max Planck Institute (MPI) for Multidisciplinary Sciences and one of the first authors of the study. In the first step, FluPol binds to the human copying machine (called RNA polymerase or Pol II), while it makes a host RNA, just after the cap has been added. This step involves both polymerases adapting their structures to be able to intimately fit together. Next, FluPol cuts off a small piece of the host RNA that includes the cap, and brings the newly created end of the snatched RNA to its active center. In the final step, FluPol extends the snatched RNA, using the viral genomic RNA as template. “When complete, the viral mRNA looks just like a host mRNA, fully functional to produce viral proteins yet invisible to the host’s immune system.”
The researchers also showed that, in addition to the two copying machines, a third partner is crucial for cap-snatching: the helper protein DSIF, which regulates the activity of the human Pol II. “Being able to observe the exact sequence and interactions of the protein partners in molecular detail closes a major gap in our understanding of how one of the most common viral pathogens is able to replicate in human cells,” summarizes Christian Dienemann, project group leader in the Department of Molecular Biology and head of the Facility for Cryo-Electron Microscopy at the MPI.
Inhibiting FluPol to combat influenza
The fact that FluPol is essential for the influenza virus to replicate also makes it its “Achilles’ heel”. Therefore, drugs for treating influenza aim, among other things, to block FluPol’s ability to perform cap-snatching, thus preventing the replication of the virus. “We found that FluPol is also less active when we altered the sites where it binds to the human Pol II-DSIF complex. We also demonstrated this inhibitory effect on FluPol in living cells,” reports Maud Dupont, who is also a lead author of the study and a PhD student in the laboratory of Nadia Naffakh at the Institut Pasteur. These interactions between the virus and the host may be used in future to develop new drugs to keep the influenza virus in check.
Dr. Christian Dienemann
Project Group Leader, Department of Molecular Biology
Head of the Facility for Cryo-Electron Microscopy, Department of Molecular Biology
Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
Email: christian.dienemann@mpinat.mpg.de
phone: +49 551 201-2819
Rotsch, A.H.; Li, D.; Dupont, M.; Krischuns, T.; Neef, U.; Oberthuer, C.; Stelfox, A.; Lukarska, M.; Fianu, I.; Lidschreiber, M.; Naffakh, N.; Dienemann, C.; Cusack, S.; & Cramer, P.: Mechanism of co-transcriptional cap-snatching by influenza polymerase. Nature (March 4, 2026).
https://doi.org/10.1038/s41586-026-10189-0
https://www.mpinat.mpg.de/5179649/pr_2604 – Original press release
https://www.mpinat.mpg.de/cramer – Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences
The image shows the 3D structure of the influenza polymerase (FluPol) stalled just before stealing t ...
Source: Alexander Rotsch
Copyright: Max Planck Institute for Multidisciplinary Sciences
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