A research team from the University of Cologne and collaborators has now shown that RNA interference, or RNAi for short, which is known to be a viral defense mechanism, also prevents the overproduction of the body’s own proteins in intestinal cells.

The study, “ER-associated RNA silencing promotes ER quality control,” was published in Nature Cell Biology.

“The endoplasmic reticulum (ER) coordinates mRNA translation and processing of secreted and endomembrane proteins,” wrote the researchers. “ER-associated degradation (ERAD) prevents the accumulation of misfolded proteins in the ER, but the physiological regulation of this process remains poorly characterized. Here, in a genetic screen using an ERAD model substrate in Caenorhabditis elegans, we identified an anti-viral RNA interference pathway, referred to as ER-associated RNA silencing (ERAS), which acts together with ERAD to preserve ER homeostasis and function.”

“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 Franziska Ottens, PhD, a postdoctoral research fellow at the University of Cologne and 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.

The researchers 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, another first author of the study and a member of Thorsten Hoppe’s team at the University of Cologne.

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