Special Molecular Pathway May Regulate Interferon mRNA Stability And The Body's Antiviral Immunity

Recently, in a research report titled "SP140–RESIST pathway regulates interferon mRNA stability and antiviral immunity" published in the international journal Nature, scientists from the University of California and other institutions revealed how the conservative transcriptional repressor SP140 indirectly regulates the stability of interferon β (IFN-β) through the RESIST protein, and also revealed the antiviral activity of SP140 itself. The relevant research results may provide a new perspective for understanding the antiviral immune mechanism.

In this study, the researchers used mouse bone marrow-derived macrophages (BMMs) and various virus strains (such as MHV68, MCMV and Sendai virus) as experimental subjects. Gene editing technology (such as CRISPR-Cas9), RNA sequencing, immunoprecipitation, flow cytometry and other technical means were used to conduct in-depth research on the interaction between SP140 and RESIST and its role in antiviral immunity. The experimental materials include BMMs, virus strains, antibodies, etc. of wild-type and SP140 knockout mice.

First, they observed the changes in IFN-β transcription levels by stimulating BMMs of wild-type and SP140 knockout mice, thereby discovering the regulatory effect of SP140 on IFN-β mRNA stability. Subsequently, the researchers used RNA sequencing technology to identify a new gene RESIST regulated by SP140, and verified the transcriptional inhibitory effect of SP140 on RESIST through a series of experiments. At the same time, they also explored how RESIST stabilizes IFN-β mRNA by interacting with the CCR4-NOT complex, and revealed the impact of this process on antiviral immunity. Finally, the researchers evaluated the antiviral activity of SP140 through infection experiments and flow cytometry.

Figure 1. Ifnb1 mRNA is stabilized in the absence of SP140.

Figure 1. Ifnb1 mRNA is stabilized in the absence of SP140. (Witt, Kristen C., et al. 2025)

The results showed that SP140 does not directly inhibit the transcription of IFN-β, but indirectly regulates the stability of IFN-β mRNA by inhibiting the expression of RESIST protein. In SP140 knockout BMMs, the stability of IFN-β mRNA increased significantly, resulting in increased IFN-β protein levels. RESIST can stabilize IFN-β mRNA by interacting with the CCR4-NOT complex to inhibit its degradation of IFN-β mRNA, which has an important impact on antiviral immunity. In addition, the researchers also found that SP140 itself has antiviral activity and can inhibit the replication of MHV68 virus. This antiviral activity is independent of its regulatory effect on IFN-β, which indicates that SP140 has multiple mechanisms of action in antiviral immunity.

In this study, the researchers revealed new roles of SP140 and RESIST in antiviral immunity. In particular, how they regulate the stability of IFN-β and the efficacy of antiviral immunity through complex interactions. This discovery not only enhances scientists' understanding of antiviral immune mechanisms, but also provides potential targets for the development of new antiviral therapies. It is worth noting that the interaction mechanism between SP140 and RESIST is quite complex, involving regulatory networks at multiple levels. In the future, the researchers will further explore the expression and function of these proteins in other immune cells or tissues, as well as their mechanism of action during different viral infections.

Reference

  1. Witt, Kristen C., et al. SP140–RESIST pathway regulates interferon mRNA stability and antiviral immunity. Nature (2025): 1-9.
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