bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–09–06
thirteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. Functional chimeric mRNAs encode proteins in mammalian immunity.
  2. CRISPR-Cas9 screen to identify genes regulating cell death.
  3. New mechanistic insight into SARM1 activation: TRIM32-mediated ubiquitination is a key lever that actuates SARM1's catalytic action, leading to axon degeneration and cell death.
  4. Direct binding of the C-terminal sequences of Bim and Bak contributes to efficient Bak activation.
  5. CDC42-pyrin interactions promote inflammasome activation and autoinflammatory disease.
  6. Unanchored ubiquitin chains promote the non-canonical inflammasome via UBXN1.
  7. Pathological Effects of NETs: Seed and soil hypothesis for inflammation spread by primed neutrophils.
  8. Lipid-mediated activation of BLT2 promotes membrane repair to prevent cell death.
  9. Methods to study PIDDosome and caspase-2 signalling.
  10. Rosa26-INDIA Identifies Early Apoptotic B Cells Before Macrophage-Mediated Efferocytosis.
  11. Real-time tracking of cell death in human intestinal organoids: A quantitative imaging approach.
  12. SARS-CoV-2 Delta variant-specific ORF3a mutations destabilize lysosomal homeostasis to trigger lysosomal damage-mediated cell death.
  13. Sustained neutrophil extracellular traps cause fracture nonunion.
  1. Nature. 2026 Sep 02.
    Functional chimeric mRNAs encode proteins in mammalian immunity.
    Olivia Venezia, Harry Kane, Gang Du, Hannah D Coughlan, Timothy M Johanson, Hongshen Wang, Pathricia Tilstam, Samuel W Kazer, Georgia Gunner, Daisy A Hoagland, Megha G Basavappa, Kanchana Ravichandran, Eren Ada, Ademi Zhakyp, Sandhya Kumar, Coco Duizer, Owen Searle, Chris Geo Provido, Leonel Joannas, Shilong Yang, Liam B Healy, Qiankun Wang, Joia Capocchi, Bahawar Sharif Dhillon, Sarah Slavoff, Liang Shan, Jorge Henao-Mejia, Ruth A Franklin, Isaac M Chiu, Jose Ordovas-Montanes, Kate L Jeffrey, Judy Lieberman, Rhys S Allan, Jonathan C Kagan, Hao Wu, Ruaidhrí Jackson.
      Individual mammalian mRNAs and proteins are typically believed to originate from single genomic loci, with isoform diversity arising through cis-splicing of pre-mRNA. Whether mRNA from distant genes can undergo trans-splicing to generate functionally relevant chimeric transcripts has remained unclear. Here we develop a pipeline combining long-read direct RNA sequencing with non-targeted and targeted validation to identify chimeric transcripts in macrophages. Chromatin conformation capture studies reveal that inflammation induces interchromosomal DNA interactions, positioning parent genes proximally to facilitate the formation of chimeric mRNA. Notably, we identify a protein-coding chimeric mRNA representing a fusion between the pore-forming protein gasdermin D (GSDMD)1,2 and a C-terminal domain translated out of frame from Tmem106a (Gsdmd-Tmem106a) in mice. We show that inflammasome priming upregulates Gsdmd-Tmem106a, with the protein localizing to the plasma membrane. After activation of the inflammasome, GSDMD-TMEM106A directly interacts with canonical GSDMD N termini to accelerate and enhance pore formation and IL-1β release. Finally, we show that GSDMD-TMEM106A balances host defence and immunopathology in vivo: its loss protects against lethal sepsis but compromises antibacterial defence, whereas overexpression enhances host protection while increasing sepsis lethality. We establish that protein-coding chimeric mRNAs formed by regulated transcript fusion events are operative during inflammation and immunity.
    DOI:  https://doi.org/10.1038/s41586-026-10982-x
  2. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00178-0. [Epub ahead of print]210 83-96
    CRISPR-Cas9 screen to identify genes regulating cell death.
    Zilong Zheng, Daichao Xu.
      Regulated cell death mediated by dedicated molecular machines, known as programmed cell death, plays important roles in health and disease. Understanding the mechanisms of cell death is crucial for elucidating the control of cellular homeostasis and developing therapies for related diseases. Despite extensive research efforts spanning decades, many aspects of cell death mechanisms remain elusive, highlighting the need for continued exploration. Here, we describe how to identify novel regulators involved in cell death pathways using a genome-wide screening approach.
    Keywords:  CRISPR-Cas9; cell death pathways; cellular homeostasis; genome-wide screening; programmed cell death
    DOI:  https://doi.org/10.1016/bs.mcb.2026.05.010
  3. Front Neural Circuits. 2026 ;20 1842408
    New mechanistic insight into SARM1 activation: TRIM32-mediated ubiquitination is a key lever that actuates SARM1's catalytic action, leading to axon degeneration and cell death.
    Hitoshi Murata, Nahoko Tomonobu, Ken-Ichi Yamamoto, Rie Kinoshita, Masakiyo Sakaguchi.
      Sterile alpha and TIR motif-containing protein 1 (SARM1) is an enzyme that cleaves nicotinamide adenine dinucleotide (NAD+) and plays a role in disrupting neural circuits through axon degeneration and cell death. SARM1 is activated by changes in the nicotinamide mononucleotide (NMN)/NAD+ ratio and by various post-translational modifications, but its complete regulatory mechanism remains poorly understood. Here, we report that tripartite motif-containing protein 32 (TRIM32) activates SARM1 through specific ubiquitination triggered by anticancer drug treatment. TRIM32 promotes the attachment of Lys27-linked ubiquitin chains to Lys173 and Lys375 within the ARM domain, which is an autoinhibitory region of SARM1. This ubiquitination by TRIM32 increases SARM1's NAD+-cleaving catalytic activity and enhances its ability to induce neurite degeneration and cell death. A mutant form of TRIM32 lacking the enzymatically active RING domain fails to promote SARM1 ubiquitination, and reducing TRIM32 levels decreases SARM1 ubiquitination. Additionally, ubiquitin-specific peptidase 13 (USP13), a known negative regulator of SARM1, can deubiquitinate SARM1. These findings suggest that TRIM32 is a key regulator of axon degeneration and cell death through its ubiquitination of SARM1.
    Keywords:  NAD + ; SARM1; TRIM32; axon degeneration; ubiquitination
    DOI:  https://doi.org/10.3389/fncir.2026.1842408
  4. Cell Death Differ. 2026 Sep 03.
    Direct binding of the C-terminal sequences of Bim and Bak contributes to efficient Bak activation.
    Dang Nguyen, Sabina Trebinjac, Tobias B Beigl, Frank Essmann, Kathryn M Murphy, David W Andrews.
      Apoptosis is regulated by Bcl-2 family of proteins through direct binding interactions at the mitochondrial outer membrane. Bak, a key cellular executioner protein in this family, differs from the other executioner proteins Bax and Bok in that it is constitutively localized at the mitochondrial outer membrane via its C-terminal sequence (CTS). Binding of the BH3-only protein Bim triggers conformational changes in Bak that lead to oligomerization and mitochondrial membrane permeabilization. However, the molecular mechanism by which Bim activates Bak remains incompletely understood. Here we demonstrate both in vitro and in cells, that efficient Bim-mediated activation of Bak requires not only the binding of the BH3-motif of Bim to the canonical BH3-binding groove of Bak, but also sequence specific, direct binding of the Bim-CTS to the Bak-CTS. These findings reveal an unexpected contribution of the Bak-CTS to the molecular control of Bak activation during apoptosis.
    DOI:  https://doi.org/10.1038/s41418-026-01848-w
  5. Nat Rev Rheumatol. 2026 Sep 02.
    CDC42-pyrin interactions promote inflammasome activation and autoinflammatory disease.
    Holly Webster.
      
    DOI:  https://doi.org/10.1038/s41584-026-01433-y
  6. Res Sq. 2026 Aug 25. pii: rs.3.rs-10666957. [Epub ahead of print]
    Unanchored ubiquitin chains promote the non-canonical inflammasome via UBXN1.
    Duomeng Yang, Jason G Cahoon, Tingting Geng, Chengliang Wang, Andrew G Harrison, Evelyn Teran, Jack L Wang, Yanlin Wang, Anthony T Vella, Vijay A Rathinam, Jianbin Ruan, Penghua Wang.
      The non-canonical caspase-4 inflammasome is a crucial anti-bacterial immune mechanism, yet, when dysregulated, may contribute to sepsis pathogenesis. Its regulation is heavily reliant on transcriptional control of caspase-4 expression. However, posttranslational regulation of the caspase-4 inflammasome remains poorly understood. Here, we report that UBX domain-containing protein 1 (UBXN1) facilitates the non-canonical inflammasome via unanchored lysine 48- or 63-linked polyUb (K48/63-Ub) chains. UBXN1 deficiency impairs the LPS-induced caspase-4 inflammasome and pyroptosis, renders mice resistant to LPS and polymicrobial sepsis. Depleting cellular unanchored polyUb with ubiquitin-specific proteinase 5 (USP5) reduces, while inhibiting USP5 enhances, caspase-4 activation in a UBXN1-dependent manner. In vitro, unanchored K48/63-Ub chains enhance LPS-induced caspase-4 enzymatic activity in a chain length- and UBXN1-dependent manner. Mechanistically, UBXN1 directly interfaces with and bridges unanchored K48/63-Ub and caspase-4, forming a tripartite complex to facilitate caspase-4 activation. Our findings uncover a previously unrecognized UBXN1- and unanchored K48/63-Ub-dependent regulatory layer in the caspase-4 inflammasome.
    Keywords:  Caspase-4; Inflammasome; UBXN1; Ubiquitination; Unanchored ubiquitin chain
    DOI:  https://doi.org/10.21203/rs.3.rs-10666957/v1
  7. Blood. 2026 Sep 02. pii: blood.2026033881. [Epub ahead of print]
    Pathological Effects of NETs: Seed and soil hypothesis for inflammation spread by primed neutrophils.
    Denisa D Wagner, Lukas Heger.
      The ability of activated neutrophils to release decondensed chromatin as neutrophil extracellular traps (NETs) in response to stimuli is conserved throughout evolution. While NETs support host defense by forming physical barriers against microbes, their toxicity can cause tissue damage. Large NET networks, generated through the activation of the NLRP3 inflammasome, the citrullinating enzyme PAD4, and neutrophil-derived enzymes, are central to the pathogenesis of numerous diseases. Chronic disorders often originate in a localized site, for example the joints in rheumatoid arthritis, or following a major inflammatory event, before progressing to distant organs, such as the heart. In this perspective, we hypothesize that circulating primed neutrophils represent the "seeds" of chronic disease, that adhere to activated vessels, the "soil" of susceptible organs. We explore the mechanisms underlying NET formation and discuss animal and human evidence supporting our hypothesis.
    DOI:  https://doi.org/10.1182/blood.2026033881
  8. J Cell Biol. 2026 Oct 05. pii: e202510004. [Epub ahead of print]225(10):
    Lipid-mediated activation of BLT2 promotes membrane repair to prevent cell death.
    Yuan Chi, Kazuko Saeki, Ken Yasukawa, Soichiro Kakuta, Tomoaki Koga, Takehiko Yokomizo.
      Various pathogenic microorganisms produce toxins that create pores in cell membranes, causing cell damage and disrupting the host epithelial barrier. Recently, we reported that mice lacking the G protein-coupled receptor leukotriene B4 receptor 2 (BLT2), which is expressed in vascular endothelial and alveolar epithelial cells, are highly susceptible to pneumolysin (PLY), a pneumococci-generated toxin. Although we clarified the protective roles of BLT2 in vascular endothelial cells, those in alveolar epithelial cells have not been elucidated. Here, we report that lipid mediator 12-hydroxyheptadecatrienoic acid (12-HHT), which is produced by membrane-damaged epithelial cells, prevents cell death by promoting membrane repair through BLT2. BLT2 promoted the release of PLY-bound plasma membranes as extracellular vesicles in a sphingomyelinase-dependent manner. Additionally, BLT2 activated Rac1 and subsequent actin polymerization, leading to resistance to cell death. Furthermore, inhibition of 12-HHT production by aspirin and treatment with a BLT2 antagonist abolished the protective effect of BLT2. These findings provide a new therapeutic strategy for bacterial infection.
    DOI:  https://doi.org/10.1083/jcb.202510004
  9. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00180-9. [Epub ahead of print]210 17-39
    Methods to study PIDDosome and caspase-2 signalling.
    Felix Eichin, Rotraud Hirschberger, Andreas Villunger, Valentina C Sladky.
      The PIDDosome multiprotein complex is formed by PIDD1 and RAIDD (alias CRADD) and serves as activation platform for caspase-2. One of the best characterized triggers for PIDDosome activation is the presence of extra centrosomes, which are frequently observed in cancer and in naturally polyploid tissues such as liver and heart. Depending on the cell type, activated caspase-2 can (1) cleave MDM2, thereby triggering a p53 response, or (2) cleave the BH3-only protein BID to induce apoptosis. Here, we describe our biochemical and cell biological tools to study the PIDDosome and caspase-2 activity. These include methods to experimentally induce PIDDosome formation in cells, as well as techniques to monitor pathway activity via protein and mRNA expression analysis, and flow cytometry. Moreover, we describe how to follow centrosome maturation for PIDDosome activation using immunofluorescence microscopy.
    Keywords:  CRADD; Caspase-2; Cell cycle arrest; Cell death; Centrosome; PIDD1; PIDDosome; Polyploidy; RAIDD
    DOI:  https://doi.org/10.1016/bs.mcb.2026.05.012
  10. Immune Netw. 2026 Aug;26(4): e33
    Rosa26-INDIA Identifies Early Apoptotic B Cells Before Macrophage-Mediated Efferocytosis.
    Uzair A Ansari, Jan Wisniewski, Christian T Mayer.
      Apoptotic cells are removed by efferocytosis, raising the possibility that in vivo apoptotic cell frequencies underestimate cell death. Rosa26-INDIA is an apoptosis reporter that detects activated caspase-3 (Casp3) via Förster resonance energy transfer (FRET) loss, but the relationship between Casp3 activation, phosphatidylserine exposure, membrane permeabilization, and efferocytic clearance remains unclear. We combined live-cell imaging and macrophage depletion to evaluate apoptotic B cell detection by Rosa26-INDIA. Live-cell imaging revealed that FRET loss preceded loss of detectable INDIA, Annexin-V positivity, and DAPI uptake. Loss of detectable INDIA occurred on average 6 and 12 min before Annexin-V and DAPI positivity, respectively, indicating that Rosa26-INDIA preferentially identifies early apoptotic cells. Consistently, macrophage depletion had limited effects on Rosa26-INDIA-based detection of apoptotic B cells under both steady-state and dexamethasone-induced conditions. These findings demonstrate that Rosa26-INDIA reports early apoptosis and suggest that macrophage-mediated efferocytosis does not substantially limit Rosa26-INDIA-based detection of apoptotic B cells under the conditions examined.
    Keywords:  Apoptosis; B-lymphocytes; Caspase 3; Flow cytometry; Macrophages; Phagocytosis
    DOI:  https://doi.org/10.4110/in.2026.26.e33
  11. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00160-3. [Epub ahead of print]210 137-156
    Real-time tracking of cell death in human intestinal organoids: A quantitative imaging approach.
    Jiyi Pang, Hojin Chang, Lachlan Whitehead, James E Vince.
      Organoids are self-renewing three-dimensional tissue models that can be derived from patient samples. Their recapitulation of the structure and function of native tissues makes them powerful tools for studying development, physiology, disease mechanisms and personalized medicine in vitro. However, quantitative assessment of cell death in organoid systems remains challenging due to their structural complexity and dynamic responses. Here, we present a robust pipeline combining real-time Incucyte® live-cell imaging with ImageJ-based quantitative analysis to measure cell death kinetics in human intestinal organoids. Organoids are cultured in the low-viscosity matrix suspension culture method, labelled with cell death-specific Incucyte® Cytotox Red Dye, and imaged via brightfield and fluorescence channels. A custom ImageJ analysis pipeline enables calculation of cell death overtime with high sensitivity and reproducibility. This approach overcomes the limitations of endpoint assays, delivering precise kinetic quantification of organoid cell death in response to cytokine stimulation, drug treatments, or genetic perturbations. The workflow is broadly applicable across diverse organoid systems and offers a scalable, standardized platform for interrogating cell death dynamics in basic and translational research.
    Keywords:  Apoptosis; Cell death; Intestinal organoids; Live cell imaging; Necroptosis; Pyroptosis
    DOI:  https://doi.org/10.1016/bs.mcb.2026.05.004
  12. Commun Biol. 2026 Aug 31. pii: 1152. [Epub ahead of print]9(1):
    SARS-CoV-2 Delta variant-specific ORF3a mutations destabilize lysosomal homeostasis to trigger lysosomal damage-mediated cell death.
    Ayushi Amin Dey, Sanchita Mishra, Vigneshwar Reddy Ashireddygari, Bharadwaj Vemparala, Anantika Chandra, Disha Jain, Narendra M Dixit, Prasad Tammineni, Sannula Kesavardhana.
      The variants of concern (VOCs) of SARS-CoV-2 emerged independently and became dominant globally at different times. Despite the emergence of multiple VOCs, the Delta variant of SARS-CoV-2 showed heightened pathogenicity and unprecedented mortality. However, the Delta variant specific mechanisms underlying its increased pathogenicity are unclear. Here, we show that variations in SARS-CoV-2 ORF3a correlate with the pathogenic potential of VOCs and drive Delta variant-specific lysosomal damage that activates inflammatory cell death. ORF3a from the Delta variant shows unique mutational patterns distinct from other SARS-CoV-2 VOCs. ORF3a-specific phylogenetic analysis reveals noticeable differences in the evolutionary trajectories of VOCs, likely reflective of their pathogenic relatedness. Unlike the Omicron variant and the ancestral Wuhan strain, Delta-specific ORF3a mutations promotes robust lysosomal damage, peripheral distribution, and membrane localization with no apparent effect on viral titers. Furthermore, Delta ORF3a mutations-induced lysosomal damage promotes both apoptosis and necroptosis activation in human cells. Structurally, these Delta variant-specific mutations appear to stabilize the ORF3a oligomers through helical packing and formation of a non-native disulfide bond, possibly facilitating their lysosomal association and damage. Overall, our observations indicate that ORF3a disrupts lysosomal homeostasis and triggers cell death, suggesting Delta-variant-specific regulation of cell fate and inflammation-associated pathogenesis.
    DOI:  https://doi.org/10.1038/s42003-026-10801-z
  13. Sci Transl Med. 2026 Sep 02. 18(865): eadx9869
    Sustained neutrophil extracellular traps cause fracture nonunion.
    Weixin Xie, Lilly-Charlotte Albertsen, Gesine Eis-Janzyk, Charlotte Kühlwein, Shan Jiang, Carsten Schlickewei, Holger Kleinertz, Ruben Augustin, Jan Sevecke, Saskia Schröder, Mayla Rickert, Samira Weisselberg, Antonia Donat, Haoyan Pan, Paul Knapstein, Verena Fischer, Melanie Haffner-Luntzer, Annika Bay, Michael Amling, Tim Rolvien, Matthias Krause, Thomas Renné, Karl-Heinz Frosch, Anke Baranowsky, Johannes Keller.
      Fracture healing is an evolutionarily conserved process that depends on the complex interplay of osteogenic, angiogenic, and inflammatory responses. Impaired bone healing is observed in up to 10 to 15% of patients with fractures and can lead to nonunion, which is the absence of bone healing. Here, we explore a role of neutrophil extracellular traps (NETs) in fracture healing and their association with nonunion. In both mice and humans, skeletal injury triggers rapid but transient NET formation at the fracture site. The combined genetic deletion of enzymes essential for NET clearance, DNase1 and DNase1-like-3, initially favors callus mineralization in the early healing phase. However, sustained NET elevation subsequently leads to impaired bone regeneration and fracture nonunion over the course of healing. Conversely, additional deletion of the NET-generating enzyme Pad4 improves bone regeneration and lowers nonunion rates. Mechanistically, NETs up-regulate cGas-Sting signaling, thereby collapsing the formation of type-H vessels, which couple osteogenesis to angiogenesis in the fracture callus. Pharmacological inhibition of cGas-Sting restored type-H vessels, enhanced bone healing, and prevented nonunion in DNase-deficient but not Pad4-deficient mice. In patients, serum NET markers declined during normal healing but were elevated in nonunion, correlating with excessive NET and STING accumulation in the callus. Therapeutically, the inhibition of NET formation with the Pad4 inhibitor GSK484 or the promotion of NET clearance with dornase alfa (recombinant DNase1) accelerated bone repair and prevented nonunion in preclinical models. These findings identify sustained NETs as a disruptor of fracture healing and a potential target for enhancing bone regeneration.
    DOI:  https://doi.org/10.1126/scitranslmed.adx9869
This page is being maintained by Thomas Krichel. It was last updated on 2026‒09‒06 at 18:12.