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Biology: Breakthrough publication in Nucleic Acids Research
Just like in a huge factory, components must also arrive in the right place at exactly the right time in living cells. A research team headed by Heinrich Heine University Düsseldorf (HHU) has examined how the transport protein Rrm4 acts as a highly precise logistics expert in the fungus Ustilago maydis. Due to its significance, the work has been published as a “breakthrough manuscript” in the renowned scientific journal Nucleic Acids Research (NAR).
Inside each cell lies the blueprint of life – DNA – well-protected in the nucleus. To produce proteins, which are the tools of the cell, a copy of this blueprint is made: the so-called messenger RNA (for short: mRNA). This copy must then be transported to where the cell needs it, for example to the protein factories.
In Ustilago maydis, which causes “corn smut” disease in maize, the mRNAs must be transported over long distances to the very tips of its thread-like filaments (the “hyphae”). Consequently, transport processes and their regulation play a central role in the functioning of these cells . To reach distant sites, an active express transport service is needed.
The transport protein Rrm4 assumes this logistical task in Ustilago maydis. It possesses three specialised “binding arms” (so-called RRMs – RNA Recognition Motifs), which it uses to bind the mRNA and load it onto membrane-enclosed organelles (endosomes). These function like freight waggons, which speed along the microtubules through the cell as though on rails.
But how does the transport protein identify which mRNAs it needs to bind to? Using the high-precision iCLIP2 method, the researchers led by Professor Dr Michael Feldbrügge from the HHU Institute of Microbiology established that mRNA possesses specific “zip codes”. Only when the binding arm of the protein fits exactly into this zip code will the package be loaded correctly and – just as important – held stably during transport.
“It was only possible to understand this process in detail through a close interlinking of disciplines. While the experimental biologists at the laboratory in Düsseldorf examined the fungi and analysed mutations, computational biologists from Würzburg tackled the enormous complexity of the data. And it was only possible to decode the millions of binding sites between protein and RNA, and identify the functionally important binding sites by means of computer-aided analysis,” says Professor Feldbrügge, corresponding author of the study now published in NAR, explaining the interplay between the various collaboration partners. He adds: “This has enabled us to decode the function of the Rrm4 protein at an unprecedented resolution. Our approach can also be used for numerous other proteins.”
The researchers established that each of the three binding arms plays a different role in mRNA recognition. The binding not only determines the transport, but also how long mRNA remains stable before it degrades. Deliberately “switching off” individual binding arms showed that the entire logistical system of the cell breaks down when there is no exact binding – the fungus can no longer grow normally.
A particular focus of the work lay on mRNAs intended for the mitochondria (the power plants of the cells). They are dependent on a constant supply of mRNAs. The researchers have now succeeded in gaining an understanding of how the nucleus, endosomes and mitochondria communicate with each other.
Intracellular networking is a key topic in the Düsseldorf-based Collaborative Research Centre CRC 1535 MibiNet, within the framework of which this research was conducted. “We have now understood how the cell uses the targeted transport of mRNA to ensure that the energy supply and communication between the different areas of the cell run smoothly,” says Professor Feldbrügge, spokesperson of the CRC.
These results in basic research into a fungus also have far-reaching implications for modern medicine. Professor Feldbrügge comments on potential perspectives for the future: “Once it is clear how mRNA is transported, recognised and stabilised, this knowledge can be used as a basis for e.g. enhancing mRNA vaccinations – which we know from the coronavirus pandemic – and making them more precise and effective.”
The journal NAR has designated the work a so-called “breakthrough manuscript”, demonstrating the significance of the study: Only the top two percent of articles submitted are awarded such a rating.
Nina Kim Stoffel, Srimeenakshi Sankaranarayanan, Kira Müntjes, Anke Busch, Julian König, Kathi Zarnack, Michael Feldbrügge; Dissecting the RNA-binding capacity of the multi-RRM protein Rrm4 essential for endosomal mRNA transport; Nucleic Acids Research, 2026, 54, gkag210
DOI: 10.1093/nar/gkag210
https://www.sfb1535.hhu.de/en/mibinet
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