According to researchers of a newly published study, a new function of a known defense mechanism discovered: (RNAi) not only fights viruses, it also regulates the protein balance of intestinal cells.

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 research team at the University of Cologne (UoC) was able to show that RNAi also intervenes in cells during protein production to maintain the protein homeostasis of the intestinal cells.

The authors explained that the body’s own protein production in the cell nucleus with the copying of DNA and the creation of the template molecule, also known as the messenger RNA (mRNA). 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, study co-author. 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 lead author Sotirios Efstathiou.

Reference:

Efstathiou, et al. “ER-associated RNA silencing promotes ER quality control.” Nature Cell Biology, 2022; 24 (12): 1714.

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