Lead author Santanu Bose, a professor in WSU’s College of Veterinary Medicine, said the researchers first found evidence that the pathway was naturally activated during infection, but that the activation was not very robust. They identified the cellular factor that switches it on and then used a synthetic factor to amplify that activation. Adding recombinant ISG15 protein significantly increased cells’ resistance to infection. The resulting mechanism strengthens the cells’ own protective machinery rather than directly targeting viral components.

Technically, the study describes a non-canonical form of ISGylation mediated by integrin-FAK signaling and triggered by extracellular ISG15. ISG15 was already known to be induced internally during viral infection and had also been observed outside cells, but its extracellular function was unclear. The experiments indicate that external ISG15 can activate a previously unknown antiviral pathway, helping cells prepare for resistance before infection spreads through surrounding tissue. The approach therefore differs from an antiviral strategy that acts directly on viral proteins or other viral targets.

RSV was the principal virus used in the peer-reviewed experiments. It is a common respiratory virus that can cause severe illness in infants, older adults and people with weakened immune systems, but the reported results concern resistance in cultured epithelial cells rather than outcomes in an animal or human trial. Unpublished follow-up experiments from Bose’s laboratory, described in the WSU news release, also demonstrated antiviral activity against influenza A and parainfluenza viruses. The supplied material does not provide the methods, measurements or limitations of those unpublished results, so their scope cannot be independently evaluated from the peer-reviewed findings.

The host-directed mechanism has a potential advantage that remains to be tested broadly: mutations that alter viral targets and allow a treatment to stop working would not necessarily disrupt a strategy operating through the host cell’s own machinery. Bose said this could make the approach less vulnerable to viral mutation and potentially useful against a broad range of viruses, but the study did not demonstrate such breadth in people or in an animal model. The researchers are developing the method as a possible antiviral therapeutic, while WSU’s Innovation & Entrepreneurship team is working with them on patent protection and commercialization. That work includes an active option for a biotechnology company to explore further development.

The investigators also see possible relevance beyond infectious disease because the pathway stimulates cellular events that could be beneficial in cancer, neurological disorders and other conditions. They are exploring whether the same method of increasing pathway activation could be applied in non-infectious therapeutic settings. Those wider applications remain under investigation: the reported peer-reviewed study established increased antiviral resistance in cells, while the proposed use of recombinant ISG15 as a treatment and its possible benefits for other diseases have not been clinically established.

The project was led by graduate students Lindsay Grace Miller, who initiated the work, and Sudiksha Pandit, together with Fulbright Postdoctoral Scholar Kim Lam Chiok from Bose’s laboratory. Professors Senthil Natesan in WSU’s College of Pharmacy and Pharmaceutical Sciences and Tanya Miura in the University of Idaho’s Department of Biological Sciences served as lead collaborators. The study was supported by the National Institutes of Health and the Washington Research Foundation, and the authors declared no competing interests.

Subject of Research: Cellular signaling by extracellular ISG15 and resistance to respiratory syncytial virus

Article Title: WSU researchers discover way to ‘crank up’ the body’s antiviral defenses

Article References: WSU researchers discover way to ‘crank up’ the body’s antiviral defenses. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: ISG15, respiratory syncytial virus, antiviral signaling, host-directed defense, epithelial cells, ISGylation, integrin-FAK signaling, viral infection, experimental study, Washington State University, researchers, discover

The challenge that motivated the work is well known to cardio-oncologists. When a patient receiving checkpoint inhibitors develops chest pain, arrhythmias, or rising cardiac troponin levels, clinicians must distinguish true ICI-myocarditis from other causes of cardiac stress in a cancer population. Current diagnosis relies heavily on biomarkers, electrocardiography, cardiac magnetic resonance imaging, and, in severe cases, endomyocardial biopsy, which is invasive and rarely performed early. Without a clear molecular understanding of what the immune system is actually doing during the attack on heart muscle, the field has lacked both precise diagnostics and rational targeted therapies. The Shanghai group set out to close that gap by examining immune cells directly, at single-cell resolution, in patients before and after the onset of disease.

Using single-cell RNA sequencing of peripheral blood mononuclear cells, the researchers profiled the circulating immune compartment of patients with ICI-myocarditis and compared it with that of cancer patients receiving checkpoint inhibitors who remained free of cardiac toxicity. The analysis revealed a striking expansion of a subset of CD8-positive T cells expressing ISG15, a protein induced by type I interferon signaling. These ISG15-positive CD8 T cells carried a strongly proinflammatory transcriptional program, suggesting they were not passive bystanders but active participants in the autoimmune assault on the myocardium. The finding was consistent across patients and was corroborated by independent flow cytometry measurements of the same cell populations.

Crucially, the ISG15-positive T cells did not appear to act alone. The single-cell data showed that their abundance at baseline correlated with proinflammatory features in monocytes, the innate immune cells that can amplify tissue damage through cytokine release and antigen presentation. Computational analysis of ligand-receptor interactions across cell types suggested that the communication between these two compartments may be mediated, at least in part, by the CCL2-CCR2 chemokine axis, a well-characterized signaling pathway that recruits monocytes expressing the CCR2 receptor toward sites of inflammation. In other words, the T cells appeared to summon and activate the monocytes, creating a self-reinforcing inflammatory loop in the heart.

To test whether these circulating cells were genuinely cardiotoxic rather than merely correlated with disease, the team performed in vitro experiments. They isolated the ISG15-positive CD8 T cells from patient blood and co-cultured them with cardiomyocytes, observing that these cells showed a high potential to induce apoptosis, or programmed cell death, in the heart muscle cells. This functional evidence supports the pathogenic role that the transcriptional data had implied: the very cells enriched in patients who develop myocarditis carry the molecular machinery to kill cardiomyocytes. It is a direct demonstration, at the cellular level, of how checkpoint inhibitor therapy can tip the immune system toward self-destruction of cardiac tissue.

The translational payoff of the study comes in two forms. The first is diagnostic. Based on the inflammatory signature identified in the multi-omics data, the researchers developed a custom panel of eight proteins measurable in blood, selected from the proteomic and cytokine profiles that distinguished ICI-myocarditis patients from other checkpoint inhibitor-treated controls. The panel showed promising performance in separating true myocarditis from patients on the same drugs who did not develop cardiac toxicity. If validated in larger, prospective cohorts, such a panel could allow oncologists and cardiologists to identify or rule out ICI-myocarditis earlier and with greater confidence than current biomarkers alone, potentially preventing the delays that contribute to the condition’s high fatality rate.

The second payoff is therapeutic. The integrated analysis pointed to JAK-STAT signaling, a central intracellular pathway downstream of many inflammatory cytokine receptors, as a shared driver of the inflammatory programs in both the ISG15-positive CD8 T cells and the activated monocytes. In mouse models of ICI-induced cardiac injury, pharmacological inhibition of the JAK-STAT pathway ameliorated cardiac dysfunction and reduced inflammatory infiltration into the heart. Remarkably, the intervention did not simply blunt the autoimmune attack; it also enhanced the response to anti-PD-1 therapy in the same models. That dual effect is significant because the ideal treatment for ICI-myocarditis would suppress the cardiac toxicity without sacrificing the anti-tumor benefit that motivated checkpoint blockade in the first place.

The chemokine axis offered a parallel therapeutic target. When the researchers blocked the CCL2-CCR2 axis in vivo, the intervention attenuated ICI-induced cardiac injury in the animal models, consistent with the idea that disrupting the recruitment of CCR2-expressing monocytes can break the inflammatory loop that damages the myocardium. Together, the JAK-STAT and CCL2-CCR2 findings suggest that ICI-myocarditis is not an undifferentiated inflammatory storm but a structured pathological circuit with defined nodes that can be pharmacologically intercepted. Each node represents a potential drug target, and several JAK inhibitors and CCR2 antagonists already exist in the clinical pharmacology arsenal for other inflammatory diseases, which could accelerate the path to clinical testing.

The study also carries implications for risk prediction before therapy begins. The observation that high levels of baseline ISG15-positive CD8 T cells are linked to the development of myocarditis raises the possibility of screening patients before they start checkpoint inhibitors, identifying those whose immune systems are already primed for interferon-driven, cytotoxic anti-cardiac responses. Such pre-treatment stratification remains speculative until prospective studies confirm the predictive value of the signature, but it fits a broader trend in immuno-oncology toward tailoring therapy to a patient’s baseline immune state rather than reacting to toxicity after it appears.

Cautions remain. The human findings rest on peripheral blood measurements, which serve as a window into the immune response but do not fully capture the inflammatory milieu inside the heart muscle itself, where tissue-resident immune populations may behave differently. The mouse models, while supportive, recapitulate only parts of the human disease. And the eight-protein diagnostic panel, however promising, will need rigorous external validation across diverse cancer types, treatment regimens, and ethnic populations before it can enter routine clinical use. Nevertheless, by integrating single-cell transcriptomics, proteomics, cytokine profiling, and functional experiments into a single coherent picture, the Zhongshan Hospital team has converted a poorly understood, frequently fatal complication into a molecularly defined disease with identifiable cellular culprits, a candidate blood-based diagnostic, and two mechanistically grounded therapeutic strategies. For the growing population of patients whose cancers are treated with checkpoint inhibitors, that transformation is a meaningful step toward making immunotherapy’s most dangerous side effect predictable, detectable, and treatable.

Subject of Research: Immune mechanisms, diagnosis, and treatment of immune checkpoint inhibitor-induced myocarditis

Article Title: Integrated multi-omics identifies distinct immune signatures with diagnostic and therapeutic implications in immune checkpoint inhibitor-induced myocarditis

Article References: Zhang, S.-L., Cai, Q.-Q., Zhang, J., Liu, Y., Lu, H., Zhang, Y.-R., Xu, Y.-C., Peng, H.-X., Chen, H.-Y., Wang, Y., Cheng, L.-L., & Ge, J.-B. (2026). Integrated multi-omics identifies distinct immune signatures with diagnostic and therapeutic implications in immune checkpoint inhibitor-induced myocarditis. Nature Communications. https://doi.org/10.1038/s41467-026-77262-0

Image Credits: AI Generated

DOI: 10.1038/s41467-026-77262-0

Keywords: immune checkpoint inhibitors, myocarditis, CD8 T cells, ISG15, monocytes, CCL2-CCR2 axis, JAK-STAT pathway, single-cell RNA sequencing, proteomics, cardiotoxicity, cancer immunotherapy, biomarkers

The research, conducted by Juhong Xie, Jiayi Lei, Qinxue Zhu, Bin Gui, Yongming Li, Yaping Wang, and Rong Huang, began with an observation made in an earlier study. Using random mutagenesis in the rare minnow, Gobiocypris rarus, a small laboratory model fish widely used in Chinese aquatic disease research, the team had identified a gene whose variation was associated with susceptibility to hemorrhagic disease. That gene encoded a protein resembling an E3 ubiquitin ligase, the class of enzymes responsible for attaching ubiquitin tags to target proteins. In the new work, detailed domain and amino acid sequence analyses confirmed that the gene truly encodes a functional E3 ubiquitin ligase, and because close relatives of the gene are found only in fish, the team designated it NHRE3, a fish-specific member of this enzyme family.

Ubiquitination is one of the cell’s most versatile regulatory tools. By stringing chains of ubiquitin, a small regulatory protein, onto specific lysine residues of a target protein, E3 ligases determine that protein’s fate. K48-linked polyubiquitin chains, in particular, serve as a molecular kiss of death: they are recognized by the proteasome, the cell’s protein-shredding machinery, and the tagged protein is rapidly degraded. Viruses have learned to exploit this system extensively. In mammals, viral proteins frequently hijack the ubiquitin pathway to dismantle signaling molecules that would otherwise trigger interferon production, the body’s first chemical alarm against infection. The question the Chinese team posed was whether fish viruses use similar tricks, and if so, through what molecular intermediaries.

The first clue came from genetics. The researchers generated rare minnows in which the nhre3 gene was knocked out, producing nhre3-null animals. When these fish were challenged with GCRV, they displayed significantly enhanced resistance to the virus compared with normal fish. In other words, removing NHRE3 made the fish harder to infect, which strongly implied that the ligase normally works in the virus’s favor. This was a striking result, because it suggested that a host-encoded enzyme was acting as an accomplice to viral infection, suppressing the very defenses it might have been expected to support. Such pro-viral host factors are prized targets for intervention, since blocking them can bolster immunity without directly attacking the virus itself.

To find out what NHRE3 actually does at the molecular level, the team turned to immunoprecipitation followed by mass spectrometry, a technique that pulls a bait protein out of the cell along with everything it physically associates with. The screen identified interferon-stimulated gene 15, or ISG15, as an NHRE3-interacting protein. ISG15 is one of the most strongly induced genes during antiviral responses across vertebrates, and in mammals it functions both as a free intracellular protein and as a modifier conjugated onto other proteins in a process called ISGylation. Its precise antiviral role in fish, however, had remained poorly understood, which made the discovery of its interaction with NHRE3 doubly significant: it implicated ISG15 in fish antiviral defense while simultaneously suggesting a mechanism by which that defense could be undermined.

Subsequent biochemical experiments established the full pathway. NHRE3 possesses genuine E3 ubiquitin ligase activity, and it uses that activity to catalyze K48-linked polyubiquitination of ISG15. Once tagged with these destruction chains, ISG15 is routed to the proteasome and degraded. The logic of the system is therefore elegantly sinister: the host produces ISG15 to fight the virus, and NHRE3, a fish-specific enzyme, eliminates ISG15 before it can do its job, thereby promoting GCRV infection. The knockout fish, lacking NHRE3, retain their ISG15 and consequently mount a stronger antiviral response, which explains their enhanced resistance to hemorrhagic disease.

Because the antiviral mechanism of ISG15 in fish had not been clearly defined, the researchers went on to investigate what ISG15 actually does downstream. Their experiments revealed that fish ISG15 can interact with IRF3, interferon regulatory factor 3, a central transcription factor in the innate antiviral response. In mammals and other vertebrates, IRF3 is activated when viral nucleic acids are detected by pattern-recognition receptors; once activated, it translocates to the nucleus and switches on the transcription of interferons and a broad panel of antiviral effector genes. The new study found that fish ISG15 promotes the expression of innate immune factors downstream of IRF3, thereby amplifying the antiviral program and exerting its protective effect against GCRV. This positions ISG15 not merely as a passive marker of interferon activity but as an active participant in the signaling cascade that drives it.

The comparison with mammalian immune evasion strategies is where the study acquires its broader evolutionary resonance. In mammals, viruses that target the ISG15 system generally do so in one of two ways: they inhibit ISGylation, the conjugation of ISG15 onto host and viral proteins, or they induce deISGylation, the enzymatic removal of ISG15 from its targets. Both strategies tinker with the modification process itself. The mechanism described in the fish study is different in kind. Here, the virus benefits from a host-encoded, fish-specific ubiquitin ligase that removes ISG15 from the cell entirely by sending it to the proteasome. The authors suggest that this may represent a more primitive or more diverse form of innate immune regulation, one in which the balance of the antiviral response is governed by the stability of ISG15 itself rather than by its conjugation state.

That interpretation carries implications for how scientists think about the origins of antiviral immunity. The immunological arms race between hosts and pathogens is ancient, predating the divergence of the major vertebrate lineages by hundreds of millions of years. Fish occupy a pivotal position in that history, and discovering that a fish-specific enzyme mediates viral immune escape through protein degradation suggests that the repertoire of evasion strategies available to viruses may be broader, and older, than the mammalian-focused literature implies. It also underscores the degree to which lineage-specific innovations, in this case a ubiquitin ligase found only in fish, can shape the outcome of infection in ways that have no direct parallel in laboratory mammals.

For aquaculture, the practical implications are immediate. Grass carp hemorrhagic disease remains a serious threat to one of the world’s largest freshwater aquaculture industries, and GCRV has proven difficult to control through conventional means. The NHRE3-ISG15 axis offers a concrete molecular target: strategies that inhibit NHRE3 activity, stabilize ISG15, or enhance IRF3-driven antiviral gene expression could plausibly be developed into breeding markers, feed additives, or therapeutic approaches that strengthen fish resistance to GCRV. The nhre3 knockout minnows generated in the study provide a proof of principle that removing this single gene measurably improves survival in the face of viral challenge. More broadly, the work demonstrates the value of studying host-pathogen interactions in non-mammalian systems, where the molecular logic of immunity may differ in instructive ways. By tracing the fate of a single protein, ISG15, from induction to ubiquitination to proteasomal destruction, the researchers have assembled a complete evasion circuit and, in doing so, illuminated one of the more ancient strategies in the long war between viruses and vertebrate hosts.

Subject of Research: A fish-specific E3 ubiquitin ligase that suppresses antiviral immunity by ubiquitinating ISG15

Article Title: A fish-specific E3 ubiquitin ligase NHRE3 suppresses antiviral immunity by degrading ISG15 via ubiquitination

Article References: Xie, J., Lei, J., Zhu, Q., Gui, B., Li, Y., Wang, Y., & Huang, R. (2026). A fish-specific E3 ubiquitin ligase NHRE3 suppresses antiviral immunity by degrading ISG15 via ubiquitination. PLOS Pathogens, 22(9), e1014544. https://doi.org/10.1371/journal.ppat.1014544

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014544

Keywords: NHRE3, ISG15, E3 ubiquitin ligase, grass carp reovirus, antiviral immunity, ubiquitination, proteasome, innate immunity, aquaculture, rare minnow, IRF3, immune evasion

The study, led by Haibin Xia of Shaanxi Normal University in Xi’an and published in Cellular and Molecular Life Sciences, centers on a protein called FAM76B, short for family with sequence similarity 76 member B. Compared with famous immune molecules, FAM76B has been an obscure figure, its functions largely unmapped. The researchers suspected it might matter for macrophage behavior, and their experiments revealed something striking: when FAM76B was absent, macrophages could still engulf apoptotic cells normally, but they could not finish the job. The swallowed corpses piled up inside the cells, undigested. In other words, the defect was not in the eating but in the digesting, a selective failure in the post-phagocytic processing of apoptotic material.

That distinction matters enormously. Engulfment is only the first half of efferocytosis; the second half requires the macrophage’s internal degradation systems to break down the ingested cargo. The cell’s primary self-cleaning and cargo-disposal pathway is autophagy, a process in which cellular material is sequestered into membrane-bound vesicles and delivered to destructive enzymes. The team found that loss of FAM76B crippled autophagic activity in macrophages, leaving them unable to properly degrade the apoptotic cells they had taken in. Because undegraded cellular debris is a well-known trigger of anti-nuclear antibodies and other hallmarks of lupus, the finding immediately suggested a mechanistic bridge between a single protein and systemic autoimmunity.

To understand how FAM76B controls autophagy, the researchers delved into the world of RNA modifications, one of the hottest areas in molecular biology. Messenger RNA molecules carry chemical tags that influence their stability and translation, the most common being N6-methyladenosine, or m6A. This tag is read and interpreted by specialized m6A-binding proteins. One such reader is HNRNPA2B1, which the team discovered was being physically restrained by FAM76B. In the presence of FAM76B, HNRNPA2B1 stays out of the cytoplasm, away from its mRNA targets. But when FAM76B is missing, HNRNPA2B1 translocates into the cytoplasm, where it can bind m6A-modified transcripts and stabilize them.

One transcript in particular proved consequential: the mRNA encoding ISG15, an interferon-stimulated gene famous for its roles in antiviral defense and inflammation. With HNRNPA2B1 free to act, ISG15 mRNA was stabilized and ISG15 protein levels climbed. Here the story took another unexpected turn. ISG15 is best known for ISGylation, a process in which it is covalently attached to other proteins, modifying their behavior. Yet the researchers showed that the suppression of autophagy they observed was independent of ISGylation. Instead, ISG15 acted through a noncanonical mechanism: it physically interacted with HSPA8, a molecular chaperone, and disrupted HSPA8’s association with BECN1, also known as beclin 1, a core component of the autophagy-initiation machinery. Severing that partnership throttled the autophagic pathway at its source.

The team then moved from cells to living animals to test whether this molecular cascade mattered for disease. Using a pristane-induced model of lupus-like disease, they compared normal mice with mice lacking Fam76b. The deficient animals fared markedly worse, developing exacerbated disease characterized by defective clearance of apoptotic cells, elevated ISG15 expression, and reduced autophagy in their macrophages. The picture that emerged was coherent: without FAM76B, the m6A reader ran loose, ISG15 accumulated, autophagy stalled, dead-cell debris accumulated, and the immune system tipped toward autoimmunity.

Crucially, the researchers did not stop at demonstrating the damage. They tested whether intercepting the pathway could undo it. When they targeted ISG15 for inhibition in the disease setting, the intervention partially restored autophagic activity, improved the macrophages’ ability to process apoptotic cells, and alleviated disease manifestations in the mice. This therapeutic experiment elevates the finding from descriptive to actionable. It suggests that ISG15, or the molecular interactions it makes with HSPA8 and BECN1, could serve as a druggable node for treating lupus and potentially other conditions in which faulty efferocytosis fuels inflammation.

The study is notable for how many layers of cell biology it stitches together into a single regulatory axis. At the top sits FAM76B, a nuclear gatekeeper controlling where HNRNPA2B1 can operate. HNRNPA2B1, in turn, interprets m6A marks on RNA to determine the lifespan of specific transcripts, including ISG15. ISG15 then reaches into the autophagy machinery through a protein-protein interaction with the chaperone-mediated arm of the pathway. Each link in this chain, from RNA modification to chaperone sequestration to vesicle formation to debris clearance, represents an area of intense research interest in its own right, and the demonstration that they form a connected circuit in macrophages offers investigators a map of previously hidden connections.

For patients with systemic lupus erythematosus, the work offers a fresh explanation for a long-recognized puzzle. Defective clearance of apoptotic cells has been implicated in lupus for decades, and elevated type I interferon activity, the very signal that drives ISG15 expression, is a hallmark of the disease. What has been missing is a precise account of how these observations connect at the molecular level. By tracing a continuous pathway from an RNA-binding gatekeeper through a chaperone-disrupting interferon-stimulated protein to the autophagy engine, the Xi’an team has supplied a candidate answer, and one that comes with an obvious intervention point.

Caution is warranted, as it always is in translational science. The findings derive from cell culture experiments and a chemically induced mouse model, and lupus in humans is far more heterogeneous, involving multiple immune cell types, genetic risk factors, and environmental triggers. Whether FAM76B levels or ISG15 activity reliably track with disease in patients, and whether blocking ISG15’s interaction with HSPA8 is feasible and safe in people, remain open questions. ISG15 also performs beneficial antiviral functions, so any therapeutic strategy would need to navigate the balance between taming autoimmunity and preserving antiviral defense. Nevertheless, the identification of a FAM76B-HNRNPA2B1-ISG15-HSPA8 axis linking RNA modification to autophagy and efferocytosis gives lupus research a new set of molecular levers to pull, and it reminds us that sometimes the key to understanding a complex disease lies in a protein whose job, until now, nobody had bothered to read.

Subject of Research: The role of the FAM76B protein in regulating macrophage efferocytosis and systemic lupus erythematosus through an m6A-ISG15-autophagy axis

Article Title: FAM76B controls macrophage efferocytosis via m6A–ISG15–autophagy axis

Article References: Weng, G., Zhang, N., Wang, L., Liu, S., Zhao, W., Cheng, J., Yang, Y., Tang, Z., Zhao, J., Yang, P., Mao, Q., & Xia, H. (2026). FAM76B controls macrophage efferocytosis via m6A–ISG15–autophagy axis. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06419-3

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06419-3

Keywords: FAM76B, efferocytosis, macrophages, autophagy, m6A, ISG15, HNRNPA2B1, HSPA8, systemic lupus erythematosus, RNA modification, apoptotic cell clearance, autoimmune disease