CD97 negatively regulates the innate immune response against RNA viruses by promoting RNF125-mediated RIG-I degradation

The G protein-coupled receptor ADGRE5 (CD97) binds to various metabolites that play crucial regulatory roles in metabolism. However, its function in the antiviral innate immune response remains to be determined. In this study, we report that CD97 inhibits virus-induced type-I interferon (IFN-I) release and enhances RNA virus replication in cells and mice. CD97 was identified as a new negative regulator of the innate immune receptor RIG-I, and RIG-1 degradation led to the suppression of the IFN-I signaling pathway. Furthermore, overexpression of CD97 promoted the ubiquitination of RIG-I, resulting in its degradation, but did not impact its mRNA expression. Mechanistically, CD97 upregulates RNF125 expression to induce RNF125-mediated RIG-I degradation via K48-linked ubiquitination at Lys181 after RNA virus infection. Most importantly, CD97-deficient mice are more resistant than wild-type mice to RNA virus infection. We also found that sanguinarine-mediated inhibition of CD97 effectively blocks VSV and SARS-CoV-2 replication. These findings elucidate a previously unknown mechanism through which CD97 negatively regulates RIG-I in the antiviral innate immune response and provide a molecular basis for the development of new therapeutic strategies and the design of targeted antiviral agents.

 

Comments:

It seems like you're discussing a study that highlights the role of the G protein-coupled receptor CD97 in the regulation of the antiviral innate immune response. The study suggests that CD97 inhibits the release of type-I interferon (IFN-I) and enhances the replication of RNA viruses in cells and mice. Here are the main points from your text:

1. **CD97's Role:** It acts as a negative regulator of the innate immune receptor RIG-I.
2. **Impact on IFN-I Signaling:** CD97's action leads to the degradation of RIG-I, suppressing the IFN-I signaling pathway.
3. **Mechanism:** CD97 upregulates the expression of RNF125, which mediates the degradation of RIG-I via K48-linked ubiquitination at Lys181 after RNA virus infection.
4. **In Vivo Studies:** CD97-deficient mice display increased resistance to RNA virus infection compared to wild-type mice.
5. **Therapeutic Potential:** Inhibition of CD97, such as with sanguinarine, effectively blocks the replication of viruses like VSV and SARS-CoV-2.

This study sheds light on a previously unknown mechanism by which CD97 negatively regulates RIG-I in the antiviral immune response. It also suggests the potential for developing therapeutic strategies targeting CD97 to combat RNA virus infections. This could be valuable in the context of finding new antiviral agents or designing targeted therapies against such infections.

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