bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–10–18
nine papers selected by
Kateryna Shkarina, Universität Bonn
  1. NINJ1-mediated membrane rupture bridges cell death to tissue inflammation.
  2. A Novel Biofilm Amyloid Ligand for Caspase-11 Drives Hyperactivation in Dendritic Cells.
  3. Clusters of GSDMD and GSDME mediate neutrophil pyroptosis in cryopyrin-associated periodic syndrome.
  4. The binding of OTULIN restrains LUBAC activity to prevent TNF-driven immunopathology.
  5. WNK1 links ionic signals to microtubule dynamics to control pyrin inflammasome assembly.
  6. Cellular self-organization orchestrates ferroptosis propagation.
  7. STING engages PKR to drive lysosomal cell death in lung ischemia-reperfusion injury.
  8. Electrostatic control of chromatin compaction safeguards against apoptotic DNA release.
  9. Long-term confinement triggers RIPK3-independent necroptosis in amoeboid cancer cells to shape tumor evolution.
  1. Biochem Soc Trans. 2026 Oct 28. 54(10): 1487-1495
    NINJ1-mediated membrane rupture bridges cell death to tissue inflammation.
    Thu Uyen Tran, Quan Thinh Le, Tuong-Khanh My Tu, Thanh Kha Phan.
      Plasma membrane rupture (PMR) is a terminal event in many forms of lytic cell death, yet was long regarded as a passive consequence of osmotic swelling and mechanical membrane failure. The identification of ninjurin-1 (NINJ1) as a key mediator of PMR fundamentally changed this view by establishing that membrane permeabilisation and terminal membrane rupture are mechanistically distinct processes. Across different cell death modalities, NINJ1 promotes the transition from membrane damage to catastrophic cellular disintegration. Structural studies have revealed how NINJ1 is restrained by autoinhibition in healthy cells and assembles into higher-order membrane-remodelling complexes following activation. However, how NINJ1 is activated and how its assemblies cooperate with the physical state of the dying cell to produce membrane rupture remain incompletely understood. NINJ1-dependent PMR also determines the release of intracellular contents, linking cell death to inflammation, host defence, tissue homeostasis and disease. Emerging evidence suggests that NINJ1 integrates molecular, metabolic and biophysical signals and can function beyond canonical cell-death pathways. Here, we discuss the molecular mechanisms governing NINJ1-mediated PMR, how diverse cell death pathways converge on this process, and how terminal membrane rupture shapes inflammatory responses, host defence and tissue pathology. We further consider unresolved mechanisms of NINJ1 activation and the therapeutic potential of uncoupling cell death from inflammatory membrane rupture.
    Keywords:  NINJ1; cell death; inflammation; membrane rupture; ninjurin-1
    DOI:  https://doi.org/10.1042/BST20260842
  2. bioRxiv. 2026 Oct 04. pii: 2026.09.29.755159. [Epub ahead of print]
    A Novel Biofilm Amyloid Ligand for Caspase-11 Drives Hyperactivation in Dendritic Cells.
    Shrutika Mintri, Guangnan Hu, Anukriti Mathur, Leah M Whiteman, Alexandre Dinis, Brian Le, Kaitlyn Grando, Patience Shumba, Vijay A Rathinam, Egil Lien, Çağla Tükel, Katherine A Fitzgerald, Stefania Gallucci.
      Bacterial biofilms drive persistent infection and chronic inflammation, yet host sensing of biofilm-derived ligands remains poorly understood. Here we identify curli amyloid, an integral component of Enterobacteriaceae biofilms, as a novel activator of the non-canonical inflammasome in human and mouse dendritic cells (DCs). Curli both primes and activates the inflammasome, directly binding caspase-11 to engage NLRP3 and drive robust IL-1β maturation without pyroptosis, establishing curli as a previously unrecognized trigger of DC hyperactivation. Mechanistically, this non-lytic signaling is marked by limited gasdermin D oligomerization without mitochondrial localization and NINJ1-dependent membrane rupture. Functionally, curli-hyperactivated DCs show enhanced migration to the draining lymph nodes in vivo, suggesting consequent augmented adaptive immunity. Finally, curli-containing biofilms also elicit IL-1β secretion without cell death, identifying bacterial amyloid as a central driver of non-lytic inflammasome activation during immune recognition of biofilms.
    DOI:  https://doi.org/10.64898/2026.09.29.755159
  3. Sci Signal. 2026 Oct 13. 19(959): eaec1743
    Clusters of GSDMD and GSDME mediate neutrophil pyroptosis in cryopyrin-associated periodic syndrome.
    ZheHao Tan, Sahand Salari Namin, Janset Onyuru, Nirav Patel, Jonathan Rodrigo Erlich, Cameron J Nowell, Jennifer Santini, Marisela Guaderrama, Maxine Nanthavongdouangsy, Jamie Casey Lee, Lori Broderick, Catherine Hedrick, William B Kiosses, Sergio D Catz, Ratnesh Lal, Yanfang Peipei Zhu, Ben A Croker, Hal M Hoffman.
      The Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a cytosolic multiprotein immune sensor that is restrained from assembling at steady state. Mutations in NLRP3 associated with cryopyrin-associated periodic syndrome (CAPS) enhance inflammasome formation and activation, resulting in neutrophil-predominant systemic and tissue inflammation. Here, we investigated how gasdermin D (GSDMD) and GSDME drive interleukin-1β (IL-1β) release, pyroptosis, and autoinflammation during constitutive and canonical NLRP3 activation in neutrophils. Mass cytometry analysis of neutrophils from patients with CAPS revealed heterogeneous subtypes with differing amounts of intracellular IL-1β. In mice, neutrophil-specific expression of activating Nlrp3 mutations orthologous to those in patients with CAPS uncovered nonredundant roles for GSDMD and GSDME downstream of inflammasome activation. Combined deletion of Gsdmd and Gsdme in these CAPS models reduced IL-1β secretion, prevented pyroptosis, and mitigated autoinflammation. Loss of both GSDMD and GSDME reduced caspase-1 cleavage and pro-IL-1β processing downstream of NLRP3 activation, whereas GSDMD deficiency alone increased cleavage of GSDME and caspase-8. Clusters of GSDMD and GSDME were closely associated with one another at the plasma membrane of activated neutrophils from CAPS mice. These findings indicate that the coordinated actions of membrane-associated GSDMD and GSDME reinforce cytosolic NLRP3 inflammasome activation to promote IL-1β secretion, lytic cell death, and autoinflammation.
    DOI:  https://doi.org/10.1126/scisignal.aec1743
  4. Mol Cell. 2026 Oct 15. pii: S1097-2765(26)00704-5. [Epub ahead of print]
    The binding of OTULIN restrains LUBAC activity to prevent TNF-driven immunopathology.
    Wenxin Lyu, Berthe Katrine Fiil, John Rizk, Majken Kjær, Max Benjamin Sauerland, Saulė Špokaitė, Biao Ma, Malin Jessen, Hanna Kulvicki, Rune Busk Damgaard, Paul R Elliott, Mads Gyrd-Hansen.
      Met1-linked ubiquitin chains (Met1-Ub), synthesized by the linear ubiquitin chain assembly complex (LUBAC) and disassembled by the deubiquitinase OTULIN, regulate inflammatory signaling and cell death. OTULIN activity prevents tumor necrosis factor (TNF)-driven autoinflammatory pathology and embryonic lethality, but the role of the direct OTULIN-LUBAC interaction remains unclear. Here, we show that mice harboring a point mutation in the OTULIN peptide:N-glycanase/UBA- or UBX-containing proteins (PUB)-interacting motif (OTULINY56A), which disrupts LUBAC binding, are viable without spontaneous pathology but are highly sensitive to TNF-induced toxicity and TNF-mediated immunopathology during Listeria monocytogenes infection. Mechanistically, the OTULIN-LUBAC interaction prevents Met1-linked autoubiquitination, thereby limiting LUBAC activity and Met1-Ub conjugation on non-LUBAC substrates. Disrupting the OTULIN-LUBAC interaction increased Met1-Ub accumulation at the TNF receptor signaling complex, which stabilized the signaling complex, increased nuclear factor-kappa B (NF-κB) signaling, and, unlike loss of OTULIN or its activity, protected from TNF-induced apoptosis. Collectively, we identify the OTULIN-LUBAC interaction as a critical brake restricting LUBAC function and Met1-Ub-dependent signaling.
    Keywords:  LUBAC; LUBAC autoubiquitination; Met1-Ub; NF-κB activation; OTULIN; PIM-PUB interaction; TNF signaling; cell death; immune pathology; inflammation
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.039
  5. Sci Adv. 2026 Oct 16. 12(42): eaeh9198
    WNK1 links ionic signals to microtubule dynamics to control pyrin inflammasome assembly.
    Genevieve Lewis, Lindsey Mayes-Hopfinger, Md Kaisar Ali, Jian Xie, Chou-Long Huang, Hanping Feng, Teresa Fernandes-Alnemri, Emad S Alnemri.
      WNK1 [with no lysine (K)] is a chloride- and potassium-sensitive kinase that regulates cellular ion homeostasis. Although WNK1 negatively regulates the NLRP3 and AIM2 inflammasomes, its role in pyrin inflammasome activation has remained unknown. Here, we identify WNK1 as a critical regulator of pyrin inflammasome assembly. In macrophages, genetic or pharmacologic inhibition of WNK1 suppresses pyrin activation without affecting pyrin dephosphorylation, demonstrating that WNK1 acts downstream of the canonical licensing step. This function occurs largely independently of the canonical SPAK/OXSR1 pathway. Mechanistically, WNK1 regulates microtubule dynamics: Its inhibition stabilizes microtubules, reduces plus-end growth, and impairs pyrin inflammasome assembly. Extracellular ionic conditions bidirectionally regulate this pathway, with hypotonic stress enhancing WNK1 activity and pyrin activation, whereas elevated extracellular potassium chloride suppresses WNK1 activity and inhibits pyrin assembly independently of osmotic stress. Together, these findings define an ion-sensitive WNK1-microtubule axis linking ionic signals to cytoskeletal dynamics to control pyrin inflammasome assembly and explain how WNK1 exerts opposing effects on distinct inflammasome pathways.
    DOI:  https://doi.org/10.1126/sciadv.aeh9198
  6. Cell. 2026 Oct 15. pii: S0092-8674(26)01142-6. [Epub ahead of print]
    Cellular self-organization orchestrates ferroptosis propagation.
    Jen-Hao Cheng, Hannah K C Co, Hao-Kuen Lin, Chia-Chou Wu, Sheng-Hong Chen.
      Self-organization generates cellular patterns that guide morphogenesis, but how it regulates collective cell fate remains underexplored. We show that cellular self-organization constrains the propagation of ferroptosis, an iron-dependent form of oxidative cell death that can otherwise spread as unbounded trigger waves. The spatial patterning of cell density and alignment encodes transcriptional programs, priming cells toward ferroptosis-sensitive or -resistant fates. Low-density, misaligned regions with elevated YAP/TEAD1 activity are sensitive, whereas high-density, aligned regions with increased NRF2 expression form propagation-resistant boundaries. Cell elongation establishes a polarized distribution of oxidizable lipids, creating peroxidation hotspots at the cell poles that promote propagation along cell alignment. In silico and pharmacological perturbations reveal that pattern-dependent susceptibility and polarized lipid organization act together to constrain isotropic waves into spatially confined, anisotropic propagation. These findings identify self-organization as a systems-level mechanism governing collective homeostasis, providing a paradigm to explore how tissue-scale organization regulates cell death in development and disease.
    Keywords:  active nematics; cellular patterns; ferroptosis; self-organization; topological defects; trigger waves
    DOI:  https://doi.org/10.1016/j.cell.2026.09.039
  7. Mol Cell. 2026 Oct 14. pii: S1097-2765(26)00667-2. [Epub ahead of print]
    STING engages PKR to drive lysosomal cell death in lung ischemia-reperfusion injury.
    Peigen Gao, Tao Wang, Yingjian Liu, Fenghui Zhuang, Chongwu Li, Guodong Wu, Yifang Dang, Huikang Xie, Chenyang Dai, Mengmeng Zhao, Deping Zhao, Xiangyang Wu, Chang Chen, Haipeng Liu, Junqi Wu.
      Stimulator of interferon genes (STING) has been implicated in multiple forms of cell death. However, the effector kinases that couple STING to these death programs remain poorly defined. Here, we show that during lung ischemia-reperfusion injury, mitochondrial DNA release engages the cyclic GMP-AMP synthase (cGAS)-STING pathway to trigger lysosomal cell death (LCD) in mouse and rat models. In human lung epithelial cells, STING oligomerization at the endoplasmic reticulum drives autophosphorylation of double-stranded RNA-dependent protein kinase (PKR) at serine 33. This phosphorylation of PKR activates IκB kinase-NF-κB signaling independently of the canonical STING-TBK1 and PKR-eIF2α pathways. In turn, NF-κB induces LAMP3 transcription, promoting lysosomal membrane permeabilization and LCD. STING-PKR signaling is also observed in patient-derived lung epithelial cells and alveolar organoids. These findings identify PKR as a non-canonical STING effector and show that blockade of STING-PKR signaling attenuates epithelial LCD and lung injury.
    Keywords:  LAMP3; PKR; STING; lung ischemia-reperfusion injury; lysosomal cell death
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.024
  8. EMBO J. 2026 Oct 16.
    Electrostatic control of chromatin compaction safeguards against apoptotic DNA release.
    Maximilian F D Spicer, Sanne Wijma, Nikki Schütte, Jan Huertas, M Julia Maristany, José Ignacio Pérez López, Lifeng Chen, Mustafa Alaabo, Michael K Rosen, Rosana Collepardo-Guevara, Daniel W Gerlich.
      Apoptosis involves extensive intracellular reorganisation to facilitate the clearance of dying cells. A key step in this process is the destruction of the genome through fragmentation by caspase-activated DNase (CAD). Rather than dispersing after CAD-mediated cleavage, DNA fragments are compacted into a dense chromatin compartment, but the underlying mechanism and biological relevance of this compaction remain unknown. Here we show that global deacetylation of histone tails promotes chromatin compaction during apoptosis, preventing DNA release into apoptotic extracellular vesicles. Using synthetic effectors that modulate nucleosome electrostatics independently of histone modifications, we demonstrate that electrostatic attraction alone is sufficient to compact and sequester fragmented chromatin. These findings reveal a mechanism by which global reprogramming of histone modifications coordinates genome fragmentation with its physical sequestration during apoptosis. Our synthetic approach further provides a tool to probe how physical forces contribute to genome organisation across diverse biological contexts.
    DOI:  https://doi.org/10.1038/s44318-026-00932-8
  9. Dev Cell. 2026 Oct 14. pii: S1534-5807(26)00351-5. [Epub ahead of print]61(10): 1952-1968.e5
    Long-term confinement triggers RIPK3-independent necroptosis in amoeboid cancer cells to shape tumor evolution.
    Wei Zhang, Ya-Jun Wang, Chunman Zuo, Junyi He, Xuying Ma, Haoran Wu, Bao-Qiong Lan, Dehui Kong, Luonan Chen, Gang Wei, Na Yang, Yuandi Fu, Dan Liu, Yan-Jun Liu, Liming Sun.
      The mesenchymal-amoeboid transition (MAT) enhances cancer cell migration and therapy resistance during dissemination through mechanically confined spaces. Using an in vitro MAT induction system combining physical confinement with a non-adhesive environment to mimic interstitial migration, we introduce "long-term MAT" (L-MAT) to describe cells sustaining MAT under prolonged pressure and show that L-MAT triggers receptor-interacting protein kinase 3 (RIPK3)-independent necroptosis. Mechanistically, the PIEZO1-STAT1 axis upregulates mixed lineage kinase domain-like pseudokinase (MLKL), whose membrane accumulation drives necroptosis in cells otherwise resistant to death-receptor signaling. Before membrane rupture, L-MAT cells show progressive migration restriction; MLKL-knockout cells bypass this checkpoint and persist as surviving clones. Spatial transcriptomics of patient tumors shows MLKL expression correlates with PIEZO1 activation and immunogenicity in less aggressive regions, while advanced malignant and metastatic clones show reduced MLKL. These findings establish MLKL as a conditional tumor checkpoint and identify the PIEZO1-STAT1-MLKL axis as a predictive biomarker and therapeutic target.
    Keywords:  MLKL; PIEZO1; RIPK3-independent necroptosis; amoeboid migration; mechanical confinement; mesenchymal-amoeboid transition; necroptosis; spatial transcriptomics; tumor checkpoint; tumor evolution
    DOI:  https://doi.org/10.1016/j.devcel.2026.09.003
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