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Virus Enzyme Links RNA Chains to Host Proteins

Bacteriophage research reveals previously unknown biological principle Viruses have the ability to reprogram suitable host cells and there take over genetic control. In order to manipulate the host’s transcription and translation system, bacteriophages – viruses specialising in bacteria – use a special mechanism: a virus enzyme links RNA chains to selected host proteins, which ultimately leads to the death of the cell. This hitherto unknown biological principle was discovered by a team of bioscientists led by Prof. Dr Andres Jäschke from the Institute of Pharmacy and Molecular Biotechnology of Heidelberg University and Dr Katharina Höfer from the Max Planck Institute for Terrestrial Microbiology in Marburg.

Viruses are infectious organic structures that do not have a complete genetic apparatus of their own. They can therefore only reproduce in suitable host cells, which they reprogram for this purpose. The mechanisms of this reprogramming are often still a mystery but of enormous scientific, medical, and economic interest. Understanding them could lead to new approaches to antiviral medicines. The interactions between RNA-binding proteins and ribonucleic acids (RNAs) are of great importance for research into viruses; RNAs play a key role in protein biosynthesis.

The Heidelberg and Marburg investigations focused on the bacteriophage T4. This virus infects the bacterium Escherichia coli, which is a model organism for research. Prof. Jäschke explains that the phage has developed “amazing strategies” to take over a bacterial cell. After T4 has entered the cell it uses, among others, three different ADP ribosyltransferases (ARTs) as biocatalysts. These ART enzymes transfer parts of a coenzyme – nicotinamide adenine dinucleotide (NAD) – onto different proteins of the host cell. That changes the function of over 30 host proteins and the cell is finally destroyed.

The T4 phage destroys Escherichia coli cells using ADP ribosyltransferases (ARTs). These ART enzymes change the function of over 30 host proteins by transferring part of the coenzyme nicotinamide adenine dinucleotide (NAD). As a new publication shows, NAD-modified RNA is accepted as a substrate as well. This procedure – the RNAylation of proteins – is a biological principle unknown until now. | Photo: Helmholtz Centre for Infection Research / M. Müsken

Prof. Jäschke’s research group discovered as early as 2014 that NAD not only exists in free form but can also be attached to certain ribonucleic acids. This discovery laid the foundation for many other research projects as NAD-RNAs were found in various organisms in different shapes and sizes. “The coenzyme nicotinamide adenine dinucleotide plays a central role in the metabolism of bacteria, as it does for higher organisms. However, the biological purpose fulfilled by this NAD modification of RNA was previously unclear,” says the Heidelberg scientist.

“We tested very different hypotheses, based on the well-known biological functions of nicotinamide adenine dinucleotide. Most of these experiments led nowhere, except for one,” says Prof. Jäschke. “Our assumption was that ART enzymes would accept not only NAD but also RNA-linked NAD as substrates and thus transfer RNA chains onto the target proteins. Although the first results from our laboratory, back in late 2016, seemed to confirm this assumption, it has only now been proven beyond doubt by a large team of researchers.” The scientists refer to this phenomenon – the attachment of an entire ribonucleic acid to a protein – as RNAylation.

In bacteriophage T4, the researchers studied an ART enzyme called ModB. They were able to show that ModB can indeed use NAD-RNAs to attach entire RNA chains to proteins in an RNAylation reaction. According to Dr Höfer, the results point to a completely new biological role for NAD-modified RNA, namely the activation of RNA for enzymatic transfer to a protein. The scientist first worked on the project at Heidelberg University and since 2020 has continued her research in Marburg.

The process appears to be essential for an efficient phage infection, as T4 mutants without ModB kill bacteria much more slowly than the phage with ModB. The ART enzyme binds different ribonucleic acids specifically to bacterial proteins involved in protein biosynthesis, as the scientists have shown using living cells. RNAylation may be part of the phage’s strategy to stop the translation of bacterial proteins, which enables the phage to regulate the biosynthesis of its own proteins, according to doctoral student Maik Wolfram-Schauerte from the Max Planck Institute in Marburg.

The current findings may also be of great significance beyond viruses, since ART enzymes are found in almost all organisms, including humans. According to the researchers, RNAylation could be a phenomenon of widespread biological relevance that goes far beyond viral infections. Also involved in the research was Prof. Dr Henning Urlaub from the Max Planck Institute for Multidisciplinary Sciences in Göttingen. The studies were funded by, inter alia, the German Research Foundation, the European Research Council (ERC) in the context of Prof. Jäschke’s ERC Advanced Grant, and the Max Planck Society. The research results appeared in “Nature”.

Originalpublikation M. Wolfram-Schauerte, N. Pozhydaieva, J. Grawenhoff, L.M. Welp, I. Silbern, A. Wulf, F.A. Billau, T. Glatter, H. Urlaub, A. Jäschke, K. Höfer: A viral ADP-ribosyltransferase attaches RNA chains to host proteins. Nature (16 August 2023)

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