In the quest to understand the intricacies of antiviral immunity, recent work has unveiled a pivotal role for the nuclear body protein SP140 in the regulation of interferon responses, uncovering a sophisticated interplay between viral evasion mechanisms and host defense strategies. SP140, a member of the SP family of proteins, has emerged not merely as a structural nuclear body constituent but as a crucial antiviral effector that functions through a dynamic balance of transcriptional repression and post-transcriptional regulation within the innate immune system.
The SP protein family, which includes well-characterized members such as SP100, has long been implicated in the host’s antiviral arsenal. SP100 is known to suppress viral genome transcription by localizing to promyelocytic leukemia (PML) nuclear bodies, sequestering viral components in transcriptionally repressive compartments. However, SP140 diverges from this mechanistic paradigm, forming distinct nuclear bodies that do not overlap with PML structures. Instead, SP140 nuclear bodies partially co-localize with nucleoli, as indicated by fibrillarin staining, suggesting a unique subnuclear niche that may underpin its specialized functions.
To investigate the antiviral potential of SP140, researchers engineered HA-tagged SP140 knock-in mice, allowing for precise localization and functional analysis of the endogenous protein. In bone marrow-derived macrophages (BMMs) from these mice, SP140 was confirmed to be expressed at physiological levels and retain its capacity to repress the interferon-beta gene (Ifnb1) following activation by the STING agonist DMXAA. Immunofluorescence assays revealed large SP140 nuclear bodies distinct from canonical PML bodies, spotlighting SP140 as a nuclear factor with a distinct role in shaping antiviral responses.
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Crucially, the antiviral function of SP140 was demonstrated through infection experiments using MHV68-GFP, a murine gammaherpesvirus engineered to express GFP as a marker of infection. Compared with wild-type macrophages, those lacking SP140 exhibited significantly increased viral infection rates, confirming SP140’s role as an antiviral barrier. Notably, this effect operated independently of type I interferon receptor (IFNAR) signaling, as SP140-deficient cells lacking IFNAR showed even greater susceptibility, underscoring SP140’s antiviral activity as distinct from canonical interferon-mediated pathways.
The study also illuminated a compensatory mechanism whereby the absence of SP140 leads to increased levels of IFN-beta transcripts, mediated by the proteins RESIST1 and RESIST2. These factors stabilize interferon mRNA, heightening the type I interferon response in SP140-deficient macrophages. In triple knockout macrophages deficient in SP140, RESIST1, and RESIST2, viral susceptibility matched that observed in interferon receptor-deficient cells, implicating this pathway as a critical backup immune response that counters viral spread when SP140-mediated restriction is lost.
Extending beyond MHV68, the antiviral scope of SP140 revealed virus-specific effects. For murine cytomegalovirus (MCMV), a subtler restriction was observed in SP140-deficient macrophages, which depended on the presence of RESIST proteins and IFNAR, suggesting that SP140’s antiviral efficacy is modulated by distinct viral contexts. Similarly, infection experiments with Sendai virus, an RNA virus encoding GFP, demonstrated enhanced viral restriction in SP140-deficient cells relying on the RESIST-mediated interferon pathway, highlighting the nuanced interplay of antiviral effectors across diverse viral families.
At the heart of this study lies the proposal that SP140’s evolution toward repressing type I interferon (IFN-I) production may represent an adaptive mechanism to calibrate immune responses and prevent deleterious inflammation. While SP100 and related nuclear body proteins exert direct antiviral effects through genome silencing within PML bodies, SP140 appears to fulfill a dual role: suppressing excessive interferon induction while maintaining direct antiviral activity through its unique nuclear localization. This balance restrains viral replication yet avoids harmful overactivation of interferon signaling pathways.
Interestingly, viruses have evolved strategies to disrupt nuclear body functions to evade antiviral restrictions. The study suggests that the SP140–RESIST axis embodies an evolutionary countermeasure, where the loss of nuclear body integrity due to viral effectors triggers a secondary, effector-triggered immunity response. This phenomenon, extensively characterized in plants, provides a ‘backup’ defense in mammals by stabilizing interferon mRNA and sustaining antiviral states despite viral attempts to dismantle primary defenses.
The molecular identity of RESIST1 and RESIST2 as RNA-binding proteins that enhance interferon mRNA stability sheds light on a pivotal regulatory checkpoint. Their involvement in fine-tuning interferon expression downstream of SP140 underscores the multilayered control of antiviral immunity, where nuclear architectural components intersect with cytoplasmic post-transcriptional regulators to sculpt an effective defense landscape.
Methodologically, the use of precise genetic models such as HA-tagged SP140 knock-in mice and combined knockouts of SP140 with RESIST and IFNAR demonstrates the power of targeted gene editing in dissecting complex immunological phenomena. Flow cytometry-based quantification of GFP-expressing viruses in bone marrow-derived macrophages provided robust evidence of SP140’s antiviral capabilities and the compensatory role of RESIST proteins, ensuring the data’s reliability and relevance.
Taken together, these findings refashion our understanding of nuclear body proteins in antiviral immunity, placing SP140 at a crossroads between chromatin-level repression and interferon-mediated antiviral amplification. The dichotomy of SP140’s functions hints at a sophisticated evolutionary dance between host and pathogen, where immune surveillance and viral evasion continuously sculpt the cellular environment.
The elucidation of the SP140–RESIST pathway opens potential avenues for therapeutic intervention aimed at modulating interferon responses and enhancing antiviral defenses, particularly in infections where nuclear body integrity is compromised. It also paves the way for deeper explorations into effector-triggered immunity in mammals, an area previously overshadowed by plant immunity research but now gaining recognition as a vital vertebrate defense strategy.
In sum, the SP140 protein exemplifies the intricate nuclear choreography underlying antiviral defense, balancing the suppression of potentially damaging interferon production with direct repression of viral genomes. The discovery of its partnership with RESIST proteins in stabilizing interferon mRNA adds a nuanced layer to the immune response, reinforcing the concept that combating viruses requires a multi-tiered and adaptable approach.
As the scientific community unravels the molecular dialogues within nuclear bodies, studies such as this redefine the boundaries of innate immunity, highlighting the crosstalk between nuclear architecture, mRNA stability, and metal signaling. In the ongoing war against viral pathogens, SP140 and its associated pathways represent new frontiers of knowledge and potential antiviral targets, promising advancements in immunology and virology alike.
Subject of Research:
Regulation of interferon mRNA stability and antiviral immunity mediated by SP140 and RESIST proteins.
Article Title:
SP140–RESIST pathway regulates interferon mRNA stability and antiviral immunity.
Article References:
Witt, K.C., Dziulko, A., An, J. et al. SP140–RESIST pathway regulates interferon mRNA stability and antiviral immunity. Nature (2025). https://doi.org/10.1038/s41586-025-09152-2
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Tags: antiviral effector mechanismsengineered mouse models for immune researchinnate immune system functionsinterferon signaling regulationnuclear body proteins and immune responsepost-transcriptional regulation of immunitySP family of proteinsSP140 and macrophage functionSP140 protein in antiviral immunitytranscriptional repression in host defenseunique nuclear bodies in immune cellsviral evasion mechanisms
