bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–07–19
nineteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. Assessing the activity of caspase-activated pannexin-1 channels by flow cytometry.
  2. Human ZBP1 is a potent inducer of cell death through mechanisms divergent from mouse ZBP1.
  3. Extracellular pneumolysin enhances the activation of cytosolic pattern-recognition receptor NOD2 through its pore-forming activity.
  4. Optimized strategies for necroptosis induction and evaluation.
  5. PAD4-generated citrullinated histones are triggers for autoinflammation in cryopyrin-associated periodic syndrome.
  6. Caspase-3 cleaves CYLD to restrict interferon signaling during mitochondrial apoptosis.
  7. Internalized components of membrane attack complexes disrupt proteostasis and acquire alarmin-like properties.
  8. A peptide-based screen for cell death inhibitors identifies the cytoprotective compound CDL36.
  9. Beta-2-microglobulin augments neutrophil phagocytosis of bacteria and apoptotic cells.
  10. Cryo-EM structures of human caspase-4 in complex with full-length gasdermin D.
  11. RIG-Ing the system to balance immune activation and inflammatory tissue damage in the airways.
  12. A core transcriptional signature of human trained immunity.
  13. Ferroptosis induction via genetic approaches - CRISPR/Cas9-based disruption on key anti-ferroptotic genes.
  14. Purine and pyrimidine-based bacterial cyclic dinucleotides egress the phagosome and activate the innate immune sensor STING.
  15. Cell death mechanisms and physiological functions.
  16. In vitro culture of intestinal organoids for cell death assessments.
  17. ESCRT-III assembles around mis-segregated DNA to protect genome stability.
  18. Flavin adenine dinucleotide is an endogenous suppressor for cytosolic DNA and RNA sensors to modulate innate immunity.
  19. The unusual suspects: the role of extracellular vesicles in host/pathogens interactions.
  1. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00124-X. [Epub ahead of print]209 41-53
    Assessing the activity of caspase-activated pannexin-1 channels by flow cytometry.
    Michael B P F Hector, Ivan K H Poon, Jascinta P Santavanond.
      Pannexin 1 (PANX1) is a ubiquitously expressed plasma membrane channel that plays an important role in maintaining cellular homeostasis through the release of small signalling metabolites. Under cell death settings, PANX1 channels can become activated by caspase-3/7 cleavage. This leads to the release of chemotactic 'find-me' signals and anti-inflammatory 'good-bye' signals. Additionally, caspase-activated PANX1 channels can regulate the fragmentation of dying cells. Due to the various cellular pathways that PANX1 channels are involved in, this membrane channel has emerged as an attractive target for novel therapeutics. To assess the effectiveness of pharmacological inhibition on caspase-activated PANX1 channels, the cell-impermeable nucleic acid-binding dye, TO-PRO-3 can be used due to its ability to be selectively taken up into apoptotic cells through caspase-activated PANX1 channels. Here we describe a robust flow cytometry-based protocol utilising Annexin A5 and TO-PRO-3 staining to accurately monitor apoptotic cell death and PANX1 channel activity. This approach can be easily adapted to investigate pharmacological compounds that have the potential to inhibit caspase-activated PANX1 channels.
    Keywords:  Apoptosis; Cell death; Flow cytometry; Pannexin-1 channels; TO-PRO-3
    DOI:  https://doi.org/10.1016/bs.mcb.2026.04.003
  2. EMBO Rep. 2026 Jul 11.
    Human ZBP1 is a potent inducer of cell death through mechanisms divergent from mouse ZBP1.
    Fei Lu, Linghuan Tang, Zichao Tian, Jialiang Tian, Yinghao Fu, Anmin Gao, Heng Dong, Jianxiang Chen, Huasong Lu, Chun Kim, Dengming Lai, Chun Zhou, Jianfeng He, Jinfa Tou, Juan Lin, Huipeng Jiao.
      Z-DNA-binding protein 1 (ZBP1) senses Z-form nucleic acids to trigger cell death and inflammation via RHIM domain-mediated interactions with RIPK1 and RIPK3. Here we show that compared to mouse ZBP1 (mZBP1), human ZBP1 (hZBP1) possesses a heightened sensitivity for inducing cell death in cells across different species and potent tumor-killing effects in vivo. In contrast to mZBP1, which signals primarily through RIPK3, hZBP1-induced cell death depends on RIPK1 in a RIPK3-independent manner. Specifically, while the scaffold function of RIPK1 is required for hZBP1-mediated apoptosis, its kinase activity is indispensable for the execution of necroptosis. Unlike mZBP1, which primarily uses only its RHIM1 domain, hZBP1 requires all three RHIM domains (RHIM1, RHIM2, and RHIM3) to trigger cell death. We further identify the C-terminal RHIM2 and RHIM3 regions as the key determinant that confers hZBP1 high sensitivity and confirm that endogenous hZBP1 promotes RIPK1-dependent cell death under pathological conditions. Together, our findings reveal an intrinsic mechanistic divergence between human and murine ZBP1 signaling and highlight the limitations of translating preclinical findings in animal models to human therapeutic strategies targeting this pathway.
    DOI:  https://doi.org/10.1038/s44319-026-00866-6
  3. Microbiol Spectr. 2026 Jul 14. e0024926
    Extracellular pneumolysin enhances the activation of cytosolic pattern-recognition receptor NOD2 through its pore-forming activity.
    Hisanori Domon, Satoru Hirayama, Toshihito Isono, Tomoki Maekawa, Yutaka Terao.
      Streptococcus pneumoniae is the leading cause of community-acquired pneumonia, meningitis, and sepsis. This bacterium produces pneumolysin, a cholesterol-dependent cytolysin that forms oligomeric transmembrane pores in the host cells. Although pneumolysin is known to exhibit proinflammatory properties, the mechanisms by which it activates innate immune responses remain to be investigated. Here, we show that extracellular pneumolysin enhances the activation of nucleotide-binding oligomerization domain 2 (NOD2), a cytosolic receptor that recognizes bacterial peptidoglycans. Experiments using HEK-Blue cell lines expressing specific pattern recognition receptors revealed that pneumolysin does not directly activate Toll-like receptors or other innate immune receptors. In contrast, our findings suggest that pneumolysin-generated membrane pores may facilitate the cytosolic entry of peptidoglycan, thereby contributing to an elevated activation of NOD2. Furthermore, pneumolysin enhances NOD1 activation in cells stimulated with a NOD1 ligand, suggesting a broader role for pore-forming toxins in innate immunity. These findings shed light on S. pneumoniae-modulated immune modulation and highlight toxin-induced immune pathways as potential therapeutic targets.IMPORTANCEThe mechanisms by which the pneumococcal pore-forming toxin pneumolysin activates innate immune responses have not been fully understood. Specifically, it remains unclear whether pneumolysin is directly sensed by Toll-like receptor 4 (TLR4) or activates the NLRP3 inflammasome. Here, we show that pneumolysin is not a direct ligand for pattern-recognition receptors. Instead, pneumolysin forms membrane pores that increase plasma membrane permeabilization, thereby amplifying innate immune signaling through multiple pathways. These pores may provide a route for the cytosolic entry of pneumococcal peptidoglycan, contributing to enhanced activation of the cytosolic receptor nucleotide-binding oligomerization domain 2 (NOD2). Additionally, membrane pores may promote the extracellular release of damage-associated molecular patterns, such as high mobility group box 1 (HMGB1), providing a mechanistic explanation for previously reported pneumolysin-induced TLR4 activation. Furthermore, pore-induced ion efflux provides a framework to explain previously reported NLRP3 inflammasome activation. Together, our findings establish membrane permeabilization as a central mechanism by which pneumolysin modulates innate immune sensing during pneumococcal infection.
    Keywords:  NOD2; Streptococcus pneumoniae; innate immunity; pneumolysin; pore-forming toxin
    DOI:  https://doi.org/10.1128/spectrum.00249-26
  4. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00125-1. [Epub ahead of print]209 67-89
    Optimized strategies for necroptosis induction and evaluation.
    Jie Lu, Haohao Lu, Sudan He.
      Necroptosis is a regulated form of cell death that relies on receptor-interacting serine/threonine-protein kinase 3 (RIPK3) -mediated phosphorylation of mixed-lineage kinase domain-like pseudokinase (MLKL). This phosphorylation drives MLKL oligomerization and membrane translocation, eventually leading to plasma membrane rupture and the release of damage-associated molecular patterns (DAMPs). Here, we outline methods to induce necroptosis by activating signaling pathways through the tumour necrosis factor receptor 1, Toll-like receptors (TLR3/4), and the interferon receptor. All pathways converge on the core event of RIPK3 activation, which further phosphorylates the effector MLKL to execute cell death. Furthermore, we describe key techniques and optimized protocols for detecting necroptotic activity and validating it with specific inhibitors, providing a comprehensive overview of both induction and evaluation strategies in necroptosis research.
    Keywords:  Cell death; MLKL; Necroptosis; Necroptosis induction; RIPK1; RIPK3
    DOI:  https://doi.org/10.1016/bs.mcb.2026.04.004
  5. Cell Death Differ. 2026 Jul 15.
    PAD4-generated citrullinated histones are triggers for autoinflammation in cryopyrin-associated periodic syndrome.
    Bregje Christiaenssen, Silke Mortelmans, Siham Baghli, Fleur Boone, Wei Xie, Arinna Bertoni, My Ha, Benson Ogunjimi, Vito Sabato, Marco Gattorno, Peter Vandenabeele, Geert van Loo, Esther Hoste, Andy Wullaert.
      Cryopyrin-associated periodic syndromes (CAPS) are autoinflammatory disorders caused by gain-of-function NLRP3 variants. Although NLRP3 inflammasomes mediate IL-1β secretion through Gasdermin D (GSDMD), we show that GSDMD deletion did not prevent autoinflammation in mice ubiquitously expressing the Nlrp3A350V variant. Inflamed skin of Nlrp3A350V-expressing GSDMD-deficient mice displayed citrullinated histone 3-containing neutrophil extracellular traps (CitH3-NETs). CitH3-NETs induced IL-1β secretion from murine Nlrp3A350V-expressing GSDMD-deficient macrophages as well as from human CAPS patient monocytes and macrophages. Blocking protein arginine deiminase-4 (PAD4) prevented CitH3 release and disabled the IL-1β-inducing NET effects, identifying CitH3 as crucial trigger. Mechanistically, CitH3-NETs activated GSDME in GSDMD-deficient Nlrp3A350V macrophages, and GSDME deletion prevented pathology in Nlrp3A350V-expressing GSDMD-deficient mice. In addition to this GSDME-dependent autoinflammation axis, PAD4 deletion also prevented autoinflammation in mice with neutrophil-specific Nlrp3A350V expression that develop CAPS in a GSDMD-dependent manner. These observations support a CAPS model in which PAD4-mediated CitH3-NET release can trigger both GSDMD-dependent and GSDME-dependent autoinflammation.
    DOI:  https://doi.org/10.1038/s41418-026-01821-7
  6. EMBO Rep. 2026 Jul 15.
    Caspase-3 cleaves CYLD to restrict interferon signaling during mitochondrial apoptosis.
    Yanis M Macé, Tiphaine Douanne, Jane Jardine, Kilian Trillet, Rosalie Moreau, Joanna Re, Cara J Ellison, Nadine Laguette, Paul R Elliott, Julie Gavard, Nicolas Bidère.
      Mitochondrial outer membrane permeabilization is a pivotal event in programmed cell death by apoptosis, leading to the activation of the cysteine protease caspase-3 (CASP3) and the release of mitochondrial nucleic acids. This release triggers the activation of the Interferon Regulatory Factor 3 (IRF3) transcription factor and the subsequent IRF3-mediated type I interferon production and cell death. CASP3 ensures apoptosis remains immunologically silent, though the mechanisms are unclear. We report that CASP3 cleaves CYLD, a deubiquitinating enzyme crucial for cell fate and inflammatory signaling. This proteolysis occurs at a site distinct from the previously reported CASP8 site, which is involved in limiting cell lysis and inflammation during extrinsic apoptosis. Although cleaved CYLD retains its enzymatic activity in vitro, knocked-in cells expressing CASP3-resistant CYLD show increased interferon signaling and enhanced cell death. Thus, a proteolytic code regulates CYLD to balance inflammation during programmed cell death.
    DOI:  https://doi.org/10.1038/s44319-026-00876-4
  7. Nat Commun. 2026 Jul 17.
    Internalized components of membrane attack complexes disrupt proteostasis and acquire alarmin-like properties.
    Guiyu Song, Zihan Ma, Matthew Fan, Liying He, Yulong Lan, Weihao Li, Zhengtao Jiang, Quan Jiang, Dylan P Noone, Andrea Nans, Kamal L Nahas, Mahsa Nouri Barkestani, Shaoxun Wang, Qianxun Wang, Pengwei Ren, Jolin Cheng, Yinuo Zang, Haitian Zhou, Justin Johnson, Clancy Mullan, Xiangyu Gong, Doryen Bubeck, Gilbert Moeckel, Michael Mak, George Tellides, Dan Jane-Wit.
      Immune effects of membrane attack complexes (MAC) have been widely attributed to their abilities to cause cell death. Here, we show that the MAC component, C9, forms non-cytolytic aggregates with pro-inflammatory effects. Intracellular aggregates of C9 are detected within inflamed tissues of patients in association with endothelial cell (EC) activation but not increased cell death. We identify NUMBL as a Rab35 effector that directly binds surface-bound C9 to promote C9 internalization and entry into the endolysosomal pathway. Within acidified endolysosomes, C9 forms insoluble aggregates that are targeted for degradative aggrephagy in a process that activates NF-κB. For C9 aggrephagy to occur, ZFYVE21, a Rab5 effector, complexes with RNF34 to bridge C9 aggregates to LC3B+ aggresome membranes. We detect C9 aggregates in vivo, and we show that a ZFYVE21-RNF34 signaling axis is required for C9 aggrephagy and NF-κB -dependent EC activation in three separate mouse models. Mice with conditional loss of ZFYVE21 in ECs show reduced aggregraphy, resulting in attenuated systemic inflammation and reduced tissue injury following skin transplantation. Our data show that the C9 component of MACs forms intracellular aggregates with alarmin-like properties.
    DOI:  https://doi.org/10.1038/s41467-026-75696-0
  8. bioRxiv. 2026 Jul 10. pii: 2026.07.09.737573. [Epub ahead of print]
    A peptide-based screen for cell death inhibitors identifies the cytoprotective compound CDL36.
    Zintis Inde, Sebastian Keppler, Jesse Gelles, Cameron S Fraser, Adam Presser, Jarvier N Mohammed, May Jung, David S Garvey, Tudor Moldoveanu, Jerry E Chipuk, Kristopher A Sarosiek.
      Small molecule inhibitors of cell death have wide-ranging potential applications, both as tool compounds in the laboratory and as clinical modulators of pathologic cell death. Previous screening efforts have identified candidate compounds targeting the pro-apoptotic, pore-forming BCL-2 family proteins BAX and BAK, but the complex interactions of these proteins at the mitochondrial outer membrane (with other proteins and the membrane itself) present challenges for compound screening. Although no inhibitors of BAX or BAK have advanced to clinical testing to date, candidate inhibitors have thus far been identified via screening of membrane-containing systems such as liposomes and isolated mitochondria. To address some of the challenges of chemical screening for apoptosis inhibitors, we conducted a small molecule screen utilizing BH3 profiling, a method that quantifies mitochondrial outer membrane permeabilization (MOMP) upon treatment with pro-apoptotic peptides derived from BCL-2 family proteins. Of over 40,000 compounds screened, we identified a series of compounds that prevent MOMP in response to pro-apoptotic peptides. The most potent of these, CDL36, binds to BAX and prevents MOMP at early timepoints. In longer term viability assays, the cytoprotective effect of CDL36 is most potent against death induced by doxorubicin, a widely used chemotherapeutic agent that causes dose-limiting cardiovascular toxicity. Our results elucidate the mechanism of action of new and existing cell death inhibitors, providing a foundation for further development of these inhibitors and potential insights into the mechanisms mediating doxorubicin toxicity in patients.
    DOI:  https://doi.org/10.64898/2026.07.09.737573
  9. Immunol Lett. 2026 Jul 17. pii: S0165-2478(26)00094-5. [Epub ahead of print] 107221
    Beta-2-microglobulin augments neutrophil phagocytosis of bacteria and apoptotic cells.
    Sofie Espersen Poulsen, Michal Magda, Anna M Blom, Mogens Holst Nissen.
      Polymorphonuclear leukocytes (PMNs), predominantly neutrophil granulocytes, are key components of the innate immune system that eliminate invading pathogens through phagocytosis and clear apoptotic cells through efferocytosis. Beta-2-microglobulin (β2m) is best known as the light chain of major histocompatibility complex class I (MHC I), where it is required for antigen presentation to CD8⁺ T cells. However, emerging evidence suggests that extracellular β2m may also regulate innate immune responses. Here, we show that extracellular β2m enhances neutrophil phagocytosis and efferocytosis. Addition of soluble β2m (50 µg/ml) increased phagocytosis of latex beads by PMNs from 23% to 31%, whereas the proteolytically cleaved variant desLys58-β2m (dK58β2m) had no effect. In contrast, both β2m and dK58β2m enhanced phagocytosis of the Gram-positive bacterium Streptococcus pyogenes and the Gram-negative bacterium Acinetobacter baumannii by more than 3.6-fold. Furthermore, both β2m variants promoted efferocytosis of apoptotic Jurkat cells in a dose-dependent manner, resulting in up to a two-fold increase that was comparable to the effect of GM-CSF. Cytochalasin D abolished β2m-mediated uptake of apoptotic cells. Pre-incubation of latex beads with β2m followed by washing did not enhance phagocytosis, and pre-incubation of PMNs with β2m followed by washing did not enhance subsequent efferocytosis of apoptotic cells. These findings indicate that β2m does not act by coating phagocytic targets or by inducing sustained neutrophil priming. Collectively, these findings identify extracellular β2m as a regulator of neutrophil-mediated phagocytosis and efferocytosis and demonstrate that proteolytic processing differentially influences these activities.
    Keywords:  Neutrophil; apoptotic cells; bacteria; beta-2-microglobulin; innate immune system; phagocytosis
    DOI:  https://doi.org/10.1016/j.imlet.2026.107221
  10. Structure. 2026 Jul 13. pii: S0969-2126(26)00190-5. [Epub ahead of print]
    Cryo-EM structures of human caspase-4 in complex with full-length gasdermin D.
    Ying Luan, Enbo Chen, Youdong Mao.
      Caspase-4 drives non-canonical inflammasome signaling by cleaving gasdermin D (GSDMD) to trigger pyroptosis. Cleavage of the interdomain linker (IDL) in caspase-4 yields distinct autoprocessed forms-p20/p12, p22/p10, and p20/p10. While both p22/p10 and p20/p10 forms of caspase-4 are capable of processing GSDMD, how these GSDMD-cleaving states are structurally organized in complex with full-length human GSDMD remains unclear. Here, we present cryo-EM structures of full-length human GSDMD bound to two human caspase-4 autoprocessed forms, p22/p10 and p20/p10. Both complexes preserve exosite-mediated recognition of the GSDMD C-terminal domain, but they display distinct catalytic-groove occupancy. In the p22/p10 complex, a residual LEED-containing IDL segment folds back into the catalytic pocket, whereas in the p20/p10 complex, the GSDMD FLTD cleavage-site linker occupies the same groove. These structures reveal how distinct IDL-processing states are associated with different modes of catalytic-groove occupancy and provide a structural framework for understanding full-length GSDMD recognition by human caspase-4.
    Keywords:  caspase-4; cryo-EM; gasdermin D; interdomain linker; stepwise maturation
    DOI:  https://doi.org/10.1016/j.str.2026.06.009
  11. Cell Syst. 2026 Jul 15. pii: S2405-4712(26)00161-4. [Epub ahead of print]17(7): 101679
    RIG-Ing the system to balance immune activation and inflammatory tissue damage in the airways.
    Alec P Pankow, Margaret A Scull, Brad R Rosenberg.
      Exposed to diverse pathogenic and non-pathogenic insults, the airway epithelium must balance effective host defense while minimizing unnecessary inflammation and tissue damage. In studies of influenza A virus infection including spatial transcriptomics, Nguyen et al. illustrate how tissue-level organization of viral sensing may tune the intensity of innate immune responses.
    DOI:  https://doi.org/10.1016/j.cels.2026.101679
  12. Cell Rep. 2026 Jul 15. pii: S2211-1247(26)00768-0. [Epub ahead of print]45(7): 117690
    A core transcriptional signature of human trained immunity.
    Katherine A Boden, Tafadzwa T J Kufazvinei, Jason Chai, Shreyas Adhikari, Injung Jang, Naveed Akbar, Robin P Choudhury.
      "Trained immunity" describes long-term functional reprogramming of innate immune cells that enhances responses to secondary challenge. However, the extent to which diverse training stimuli converge on shared transcriptional programs remains unclear. Here, we systematically analyzed publicly available RNA-sequencing datasets from diverse human trained-immunity models to define both baseline and restimulated responses of trained cells. Cross-dataset comparisons identified shared transcriptional and functional programs, indicative of common baseline and trained immune states. By integrating gene-expression data across models, we derived a consensus signature of human trained-immunity, which was validated in independent bulk and single-cell datasets. Enrichment analyses showed activation of pro-inflammatory and metabolic programs, including modulation of cellular iron homeostasis and robust increases in chemokine CCL7 expression, alongside suppression of anti-inflammatory, resolution-associated genes. These findings indicate that diverse training stimuli converge on core, shared gene-expression programs and support a two-layer model in which durable baseline reprogramming precedes exaggerated inflammatory responses upon restimulation.
    Keywords:  CP: immunology; RNA-sequencing; gene signature; innate immune memory; trained immunity; transcriptional signature
    DOI:  https://doi.org/10.1016/j.celrep.2026.117690
  13. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00158-5. [Epub ahead of print]209 91-103
    Ferroptosis induction via genetic approaches - CRISPR/Cas9-based disruption on key anti-ferroptotic genes.
    Jiashuo Zheng, Weijia Zhang, Marcus Conrad.
      Unlike apoptosis, necroptosis, or pyroptosis which are executed by dedicated proteins, ferroptosis is a distinct form of regulated cell death driven by lipid peroxidation downstream of metabolic dysfunction. In most physiological settings, the cyst(e)ine/glutathione/glutathione peroxidase 4 (GPX4) axis constitutes the central anti-ferroptotic machinery, and disruption of this axis is usually sufficient to trigger ferroptosis. For in vitro studies, commonly employed ferroptosis inducers include erastin, which blocks cystine uptake by targeting system xc-, and (1S,3R)-RSL3, which inhibits GPX4 activity. However, both compounds exhibit off-target effects - erastin can activate voltage-dependent anion channels in mitochondria, whereas (1S,3R)-RSL3 affects other selenoproteins in addition to GPX4. Thus, genetic approaches to induce ferroptosis provide a valuable complement to chemical inducers by excluding off-target concerns. Here, we describe an efficient CRISPR/Cas9-based strategy to generate SLC7A11- and GPX4-knockout HT1080 cells. These knockout lines require routine culture in medium supplemented with β-mercaptoethanol or liproxstatin-1, while withdrawal of these supplements readily induces ferroptosis.
    Keywords:  CRISPR/Cas9; Ferroptosis; GPX4; HT1080 cells; Knockout; SLC7A11
    DOI:  https://doi.org/10.1016/bs.mcb.2026.05.002
  14. Immunity. 2026 Jul 17. pii: S1074-7613(26)00274-8. [Epub ahead of print]
    Purine and pyrimidine-based bacterial cyclic dinucleotides egress the phagosome and activate the innate immune sensor STING.
    Stephanie A Ragland, Katherine E Lindblad, Yao Li, Joon H Choi, Daniel Okin, Joshua Q Mao, Desmond Richmond-Buccola, Daniela R Coronado, Madison R Brown, Scott B Snapper, Philip J Kranzusch, Jonathan C Kagan.
      Toll-like receptors (TLRs) are considered general sensors of bacterial encounters. Here, we examined whether other pattern recognition receptors are commonly activated during bacterial infection. TLR-independent interferon (IFN) responses were induced in macrophages in response to diverse bacterial encounters. Of the cytoplasmic receptor families examined, the cyclic dinucleotide (CDN) sensor STING was required for IFN responses to evolutionarily diverse bacteria. Various bacterial CDNs were present in murine tissues; these activated stimulator of interferon genes (STING) after bacteriolysis in phagolysosomes in a manner requiring two CDN transporters. Importantly, bacterial CDNs were increased in colonic biopsies from patients with inflammatory bowel disease. Systemic delivery of dead, CDN-laden bacteria promoted anti-tumor immunity in mice. Detection of diverse CDNs, including pyrimidine-based CDNs, was an evolutionarily conserved feature of STING, with distinct binding modes for purine- and pyrimidine-based CDNs. Thus, a phagocytosis-CDN-STING connection places cytoplasmic sensing as a common outcome of host-bacteria interactions that set the immune tone of a tissue, with implications for host defense.
    Keywords:  2′3′-cUMP-AMP; LRRC8A; STING; bacteria; cGAS; cyclic dinucleotides; interferon; macrophage; phagosome; toll-like receptor
    DOI:  https://doi.org/10.1016/j.immuni.2026.06.023
  15. Cell Chem Biol. 2026 Jul 16. pii: S2451-9456(26)00240-0. [Epub ahead of print]33(7): 887-888
    Cell death mechanisms and physiological functions.
    Cell Chemical Biology editorial team
      Cell death research has evolved beyond understanding the fate of damaged cells to reveal a diverse network of regulated pathways with complex mechanisms that shape physiology and disease. This special issue highlights emerging mechanisms, physiological functions, and intricate crosstalk across the expanding landscape of cell death programs.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.06.016
  16. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00157-3. [Epub ahead of print]209 55-65
    In vitro culture of intestinal organoids for cell death assessments.
    Luying Zheng, Daichao Xu.
      In vitro cultured organoids exhibit highly similar structures to their corresponding tissues and organs. Intestinal organoids derived from intestinal stem cells faithfully recapitulate the key characteristics of native intestinal epithelium, including morphological features, physiological functions, and personalized responses to specific stimuli. This protocol focuses on the isolation of intestinal crypts from murine intestinal tissues and the subsequent establishment of stable intestinal organoid cultures in vitro. Furthermore, propidium iodide (PI) staining coupled with high-content imaging analysis was employed to characterize organoid cell death. This optimized protocol provides a robust platform for high-throughput screening of intestinal disease-related cell death factors, thereby facilitating mechanistic investigations into intestinal pathogenesis.
    Keywords:  Immunostaining; Intestinal organoid; Organoid cell death; Propidium iodide staining
    DOI:  https://doi.org/10.1016/bs.mcb.2026.05.001
  17. Nat Struct Mol Biol. 2026 Jul 15.
    ESCRT-III assembles around mis-segregated DNA to protect genome stability.
    James Glover, Nathaniel Talledge, John McCullough, Akram Alian, Jessica B A Sadler, Sahil Kamboj, Nathaniel W M Dempsey, Thomas G Laughlin, Henry C Nguyen, Dawn M Wenzel, Matthew S Lalonde, Elliott L Paine, Barbie Ganser-Pornillos, Leandro N Ventimiglia, Dollie LaJoie, Janet H Iwasa, Christopher P Arthur, D John Lee, Frank R Moss, Meera Venkatesh, Lydia M Arnold, Jarrod S Johnson, Katharine S Ullman, Adam Frost, Wesley I Sundquist, Juan Martin-Serrano.
      Chromosome mis-segregation events that remain unresolved during cytokinesis threaten genome stability. Persistent ultrafine DNA bridges engage the Aurora B-dependent abscission checkpoint (termed NoCut), which delays abscission by phosphorylating components of the ESCRT complex. Here we show that NoCut surveillance repurposes human ESCRT-III, the membrane-remodeling complex that seals the reforming nuclear envelope in anaphase. In response to persistent ultrafine DNA bridges, ESCRT-III transfers from the reforming nuclear envelope to the mis-segregated DNA bridge and ESCRT-III complexes protect the DNA from damage, as evidenced by increased DNA damage upon CHMP1B depletion. Complementary in vitro assembly reactions show that the human ESCRT-III proteins CHMP1B and IST1 can copolymerize into double-stranded filaments that encase double-stranded DNA and nucleosomes and prevent nuclease digestion and cGAS recognition, demonstrating that ESCRT-III complexes can directly bind and protect DNA. Lastly, cells expressing a DNA-binding mutant of CHMP1B exhibit cytokinesis failure and binucleation when ultrafine DNA bridges persist, revealing a mechanism of safeguarding genome stability.
    DOI:  https://doi.org/10.1038/s41594-026-01841-4
  18. Immunity. 2026 Jul 13. pii: S1074-7613(26)00261-X. [Epub ahead of print]
    Flavin adenine dinucleotide is an endogenous suppressor for cytosolic DNA and RNA sensors to modulate innate immunity.
    Yao Wang, Yanyan Shen, Jiayu Liu, Qi Qi, Yue Guo, Yunying Wang, Boyang Xie, Chunyan Yan, Yanhong Liu, Zhi Jin, Ruibo Wang, Aiping Cao, Juncheng Li, Zengqing Song, Jing Chen, Qiuying Han, Yingjie Zhu, Kun Zhang, Taixia Wang, Tao Li, Xin Pan, Xinhua He, Tao Zhou, Ailing Li, Xuemin Zhang, Na Wang, Qing Xia, Weina Zhang.
      Cytosolic DNA and RNA sensing is crucial for innate immunity, playing essential roles in pathogen defense and autoinflammation induction. We reported the endogenous metabolite flavin adenine dinucleotide (FAD) as a molecular brake restraining both cytosolic DNA and RNA sensing. It bound directly to cytosolic nucleic acid sensors cyclic GMP-AMP synthase (cGAS) and retinoic acid-inducible gene I (RIG-I), occupying catalytic pockets to suppress their activity and downstream immune responses. Physiologically, FAD prevented self-nucleic acid-induced sterile inflammation and maintained immune homeostasis. FAD deficiency due to FAD synthase (FLAD1) ablation exacerbated auto-inflammation and cellular senescence. Upon viral infection, reduced FLAD1 activity lowered FAD amounts, which removed its inhibitory control over DNA and RNA sensors, thus facilitating extensive interferon-I (IFN-I) signaling activation. Consequently, FLAD1 depletion strengthened the innate immune response and protected mice from viral infection. Our findings identify FAD as a natural suppressor of both cytosolic DNA and RNA sensing, offering therapeutic potential for inflammatory diseases.
    Keywords:  RIG-I; autoinflammation; cGAS; cellular senescence; cytosolic DNA and RNA sensing; flavin adenine dinucleotide; immune homeostasis; type I interferon; viral infection; vitamin B2
    DOI:  https://doi.org/10.1016/j.immuni.2026.06.010
  19. Curr Opin Microbiol. 2026 Jul 17. pii: S1369-5274(26)00091-3. [Epub ahead of print]93 102797
    The unusual suspects: the role of extracellular vesicles in host/pathogens interactions.
    Manon Le Fé, Matteo Bonazzi.
      Extracellular vesicles (EVs) released by host cells are emerging as central effectors of antibacterial immunity. Through distinct biogenetic pathways, they carry selectively sorted proteins, lipids, nucleic acids, and metabolites whose composition is dynamically reshaped by the physiological state of the producing cell. Infection-derived EVs propagate inflammatory and antimicrobial signals to bystander cells, intercept secreted bacterial toxins as molecular decoys, and prime adaptive responses through antigen presentation. Conversely, bacterial pathogens have evolved counterstrategies that suppress EV release, divert cargo loading, or co-opt EVs as carriers of virulence factors, thereby converting a host defence program into a pathogenic asset. The net outcome of EV-mediated communication is highly context-dependent, varying with pathogen species, host cell type, tissue environment, and infection stage. Here, we first review evidence that EVs serve as bona fide instruments of host defence, then describe how different bacterial pathogens subvert these same pathways, and discuss methodological limitations and translational opportunities for targeting infection-derived EVs.
    DOI:  https://doi.org/10.1016/j.mib.2026.102797
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