Antiviral defence regulates intestinal function and overall gut health

07.12.2022 TopNews Prof. Dr. Thorsten Hoppe

To study gut barrier function, worms were fed a blue dye. Worms with functional ER quality control mechanisms (left) show the dye only in the intestine. In contrast, animals with a defect in ER quality control (right) show a distribution of the blue dye from the intestine to other parts of the body. This is an indication of a disturbed intestinal barrier.

New function of a known defence mechanism discovered: RNA interference not only fights viruses, it also regulates the protein balance of intestinal cells / Publication in ‘Nature Cell Biology’

Besides the skin, the digestive tract is the tissue that is most exposed to environmental influences such as bacteria and viruses. Therefore, cells that form these barriers to the interior of the body also have special defence mechanisms. A research team led by Professor Dr Thorsten Hoppe has now shown that RNA interference, or RNAi for short, which is known to be a viral defence mechanism, also prevents the overproduction of the body’s own proteins in intestinal cells. The study ‘ER-Associated RNA Silencing Promotes ER Quality Control’ has been published in the journal Nature Cell Biology.

RNAi is able to recognize, bind, and ultimately degrade RNA from viruses. This prevents the production of viral proteins. With the help of green fluorescent proteins and further analyses in the nematode Caenorhabditis elegans, the UoC research team was able to show that RNAi also intervenes in cells during protein production to maintain the protein balance (protein homeostasis) of the intestinal cells. The body’s own protein production starts with the copying of DNA and the creation of the template molecule, also known as the messenger RNA (mRNA), in the cell nucleus. The mRNA is then taken to the endoplasmic reticulum (ER), where a protein is produced from the template molecule. As in a factory, the manufactured proteins are subject to a strict quality control. Deficient proteins are exported from the ER and degraded to avoid cellular waste and extensive negative consequences for the physiology and functionality of the cell as well as the tissue.

‘We observed that the RNAi mechanism specifically degrades messenger RNAs at the ER before the protein is even produced. This serves to protect the ER from being overloaded by too much production,’ said Dr Franziska Ottens, one of the first authors of the study. The scientists thus found a new mechanism to regulate protein production.

The interplay between RNAi and previously known ER quality control systems appears to be important for overall intestinal health. This is shown by the fact that simultaneous failure of both mechanisms impairs the important barrier function of the gut. The study results also suggest a link between ER functionality and quality control, which are important for protection against viral infection. For example, RNA viruses such as SARS-CoV use the ER for replication.

‘We were able to significantly suppress viral loads by specifically overstressing the ER. The interplay of protein homeostasis, RNAi, and viral infection could be an important approach for the prospective research and treatment of viral diseases,’ said doctoral candidate Sotirios Efstathiou, a member of Thorsten Hoppe’s team and another first author of the study.

The research was conducted at the CECAD Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases at the University of Cologne. It was funded by the German Research Foundation (DFG) in the framework of the German Excellence Strategy and by the European Research Council. Furthermore, support from the Cologne Graduate School of Aging Research and the Alexander von Humboldt Foundation made the research possible.

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ER-Associated RNA Silencing Promotes ER Quality Control, Efstathiou S, Ottens F, Schütter LS, Ravanelli S, Charmpilas N, Gutschmidt A, Le Pen J, Gehring NH, Miska EA, Bouças J, Hoppe T. Nature Cell Biology, 2022