# The CD97-PPM1G axis dampens antiviral immunity by dephosphorylating IRF7 in type I interferon pathway

## TL;DR

The study reveals how CD97 and PPM1G work together to weaken the body's antiviral defenses, offering new targets for antiviral therapies.

## Contribution

The paper identifies the CD97-PPM1G axis as a novel regulator of antiviral immunity through IRF7 dephosphorylation.

## Key findings

- CD97 recruits PPM1G to dephosphorylate IRF7, inhibiting the IFN-I response.
- Mice lacking CD97 show increased resistance to viral infections.
- Sanguinarine reduces CD97 expression and viral replication.

## Abstract

The activation of type I interferon (IFN-I) signaling is crucial for defending host cells against viral infections. A comprehensive IFN-I response necessitates the activation of several cellular factors, among them Interferon Regulator Factor 7 (IRF7). Nonetheless, the mechanisms governing IRF7 inactivation in response to viral infection remain largely unknown. Here, we illustrate that Cluster of differentiation 97 (CD97), a G protein-coupled receptor, interacts with PPM1G via intracellular Arg-819 and Arg-822 residues. PPM1G then recruits and dephosphorylates IRF7, leading to its inhibition. CD97-mediated inactivation of IRF7 impedes its translocation into the nucleus and subsequent activation of IFN-I, ultimately promoting the viral replication. Moreover, mice lacking CD97 display heightened resistance to viral infection. The compound sanguinarine (SANG) hinders viral replication by dampening CD97 expression. This study provides a basis for CD97 as a potential antiviral target and SANG as a candidate antiviral small molecule drug.

Upon viral infection, the body’s first line of defense is the IFN-I response, a critical immune signaling pathway that defends host cells against invading pathogens. However, this system is tightly regulated by innate immune-inhibiting molecules within the host. The significance of this study lies in its identification of the CD97-PPM1G axis as a key regulator that suppresses the IFN-I response. Specifically, the research elucidates the molecular mechanism by which CD97 recruits the phosphatase PPM1G, which subsequently dephosphorylates the transcription factor IRF7. This dephosphorylation inhibits IRF7, thereby suppressing the entire IFN-I signaling cascade. In addition, the study employed CD97 knockout mice, which demonstrated significantly enhanced resistance to viral infection, confirming its role in vivo. Furthermore, the compound sanguinarine effectively hinders viral replication by dampening CD97 expression. These findings not only advance our theoretical understanding of immune homeostasis but also provide a solid foundation for developing antiviral strategies for both humans and animals.