Researchers in Japan have identified a striking new way immune cells strip DNA out of dying neighbors, a process they call nucleocytosis that directly ties cell death to antiviral signaling. The work, led by investigators at the University of Tokyo and published in Nature Communications, shows macrophages physically extract nuclear DNA from doomed cells instead of waiting for the nucleus to fall apart. The discovery matters because that stolen DNA plugs straight into a key alarm system that drives inflammation and type I interferon responses.
The findings arrive as scientists try to explain how self DNA reaches sensors that normally detect viruses, and why those pathways sometimes misfire in autoimmune disease. Nucleocytosis adds an unexpected mechanical step to that story, raising fresh questions about how immune cells decide when self DNA is a danger signal and when it is harmless debris.
How nucleocytosis rewrites the script on dying cells
The Nature Communications team defines nucleocytosis as macrophage mediated extraction of nuclear DNA from dying cells, based on live cell imaging and perturbation experiments that tracked the transfer of genetic material out of the nucleus and into immune cells, according to primary data from the journal. Instead of the classic picture where a dying cell’s nuclear envelope disintegrates and its contents spill out, the group reports that macrophages reach into intact or only partially dismantled nuclei and pull out selected DNA. A linked PubMed abstract confirms that macrophages extract nuclear DNA via nucleocytosis and that the work sits in Nature Communications with a specific DOI and article number, according to the government hosted record at PubMed.
Mechanistically, the authors connect this extraction process to the cGAS–STING pathway, showing that the DNA obtained through nucleocytosis activates cGAS, triggers STING, and culminates in type I interferon production, according to the experimental analysis described in the DOI linked version of the paper. An associated institutional press release from the Institute of Medical Science at the University of Tokyo states that nucleocytosis involves selective nuclear DNA extraction without classical nuclear envelope breakdown, emphasizing that this route for self DNA delivery to cGAS differs from previously described cell death pathways, according to the statement from the University of Tokyo. Together, these records present nucleocytosis as a distinct phenomenon that could reshape how immunologists think about the physical journey of DNA from a dying nucleus to cytosolic sensors.
Lysosomes, PPT1 and calreticulin: the machinery behind the rip
The PubMed abstract reports that lysosomal malfunction and inhibition of the enzyme PPT1 are involved in nucleocytosis, indicating that the extraction of nuclear DNA depends on intact degradative pathways inside macrophages, according to the description at PubMed. When lysosomes fail or PPT1 is blocked, the study records changes in how efficiently macrophages can pull DNA from dying nuclei, which ties a classic waste disposal organelle to this newly described DNA transfer route. That same abstract highlights calreticulin as another component of nucleocytosis, suggesting that a protein best known as an “eat me” signal and chaperone also shapes how nuclear DNA is recognized and extracted during cell clearance.
These mechanistic details matter because they anchor nucleocytosis in pathways that are already under therapeutic scrutiny in inflammatory disease. A high authority review on the cGAS–STING pathway describes this signaling axis as a therapeutic target in inflammatory conditions and stresses that self DNA in the cytosol is a key trigger of cGAS activation, according to the analysis from Nature Reviews Immunology. By pointing to lysosomes, PPT1 and calreticulin as gatekeepers of nuclear DNA extraction, the nucleocytosis work hints that drugs touching these systems might unintentionally modulate interferon responses, although the primary data remain preclinical and do not include clinical trial outcomes.
From nuclear DNA to cGAS–STING alarms
The Science review that the nucleocytosis paper cites frames cGAS as a DNA sensor with expanding roles in immunity and inflammation and identifies the route by which nuclear DNA becomes available to cGAS as a central unresolved issue, according to the synthesis in Science. That review notes that cGAS must somehow encounter self DNA without constantly misfiring, and that distinguishing self from non self DNA is a persistent problem for the pathway. By showing that macrophages actively extract nuclear DNA from dying cells and present it into a context that activates cGAS, the Nature Communications work offers one concrete delivery route that fits into this open question from the earlier review.
Downstream of cGAS, STING connects DNA sensing to broader inflammatory programs and has documented roles in infection, inflammation and cancer, according to a seminal review that details STING activation through TBK1 and IRF3 and the resulting interferon programs in Nature Reviews Immunology. A separate high authority review focused on systemic and organ specific diseases reports that cGAS–STING activation occurs in multiple disease settings, reinforcing that this pathway is not limited to antiviral defense, according to the evidence summarized in Nature Reviews Nephrology. In that context, the direct link between nucleocytosis and cGAS–STING activation reported in the Nature Communications paper raises the possibility that how macrophages handle nuclear DNA from dying cells could influence disease processes far beyond a single infection.
How nucleocytosis compares with DNA spewed as immune traps
Nucleocytosis is not the first time immunologists have watched DNA take on unexpected roles outside the nucleus. Neutrophils, which are described as the most abundant circulating blood cell type in humans and the first white blood cells recruited to sites of inflammation, have a well documented ability to use their own DNA as an antimicrobial net, according to an analysis of neutrophil enhancers and autoimmune disease in a primary neutrophil study. That work describes how neutrophils expel chromatin structures that trap pathogens that are difficult to engulf, such as certain fungal organisms. An intravital microscopy study of cutaneous innate responses adds that pathogen killing can occur through phagocytosis, release of reactive species, or expulsion of nuclei through NETosis in the skin, according to the observations reported in Immunology & Cell Biology.
These neutrophil extracellular traps, or NETs, form through a process that begins with nuclear vesiculation followed by rupture and disintegration of the nuclear envelope, resulting in characteristic structures during ETosis, according to a review of nuclear mechanobiology and immune functions in a mechanobiology analysis. In contrast, the University of Tokyo press release on nucleocytosis states that macrophages extract nuclear DNA from dying cells without classical nuclear envelope breakdown, and the Phys.org summary of the same work repeats that nucleocytosis occurs without nuclear envelope breakdown and has implications for autoimmune disease, infection and cancer, according to the institutional framing on Phys.org. Together, these records set up a clear contrast: NETosis relies on a cell sacrificing its own nucleus and breaking its nuclear envelope, while nucleocytosis describes another cell reaching into a dying neighbor’s nucleus and pulling DNA out while the envelope structure remains largely in place.
Why a new DNA extraction route matters for disease
The cGAS–STING reviews that the nucleocytosis paper references make clear that self DNA in the cytosol is a central trigger for inflammation in multiple diseases, yet they also stress that the route by which nuclear DNA becomes available to cGAS has been a key unresolved issue, according to the synthesis in Science and the disease focused overview in Nature Reviews Nephrology. By documenting a macrophage driven extraction process that feeds nuclear DNA directly into cGAS–STING and type I interferon responses, the Nature Communications study provides a concrete mechanism that could help explain how dying cells influence chronic inflammation. However, the available sources do not report clinical trial data on targeting nucleocytosis, and institutional materials from the University of Tokyo frame autoimmune, infection and cancer links as implications rather than proven outcomes, according to the press statement at the Institute of Medical Science.
The broader literature also shows that DNA based immune responses often bring tradeoffs. NETs, for example, are described as effective against different pathogens including viruses and as fundamental components of innate defense in severe infections such as sepsis, but several studies warn that excessive NET generation can cause endothelial damage, impair tissue repair and contribute to autoimmune disease, according to analyses hosted at PMC on viral infection and NET related pathology. Against that backdrop, nucleocytosis looks like another way DNA can leave the relative safety of the nucleus and enter inflammatory circuits. The current record does not yet show whether nucleocytosis will prove protective, harmful, or context dependent in human disease, but by tying a physical extraction event to a well studied signaling axis, the Nature Communications work gives immunology a new process to scrutinize as scientists try to separate helpful alarm signals from those that push the body toward chronic inflammation.
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*This article was researched with the help of AI, with human editors creating the final content.
