bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–03–22
fourteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. Mitoxyperilysis: fasting-induced cell death in immunometabolism and disease.
  2. Transcending cell death - The diverse roles of necroptosis signal adaptors in pathogen infection.
  3. ATP13A2 restrains macrophage NLRP3 inflammasome activation to repress neurodegeneration via modulating mitochondrial homeostasis.
  4. Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
  5. Cofilin-1 is a redox-sensitive guard of the NLRP3 inflammasome.
  6. Subcellular calcium dynamics and organelle perturbations in resistosome-mediated cell death.
  7. Caspase-3/7 deficiency results in enhanced intestinal inflammation and reduced tumorigenesis.
  8. Glycogen phosphorylase L confers metabolic flexibility in neutrophils to fight fungal infections in nutrient-deprived tissues.
  9. ZNFX1 uses two-component ubiquitin circuitry to quarantine viral RNA.
  10. Atomic-level architecture and assembly mechanism of high-order structures of RIPK1 fibril revealed by integrated structural biology.
  11. GEF-H1 upon microtubule destabilization drives ZBP1-dependent necroptosis.
  12. Caspase-mediated DDX46 cleavage unchains antiviral immunity.
  13. Mitochondrial DNA release via VDAC1 in keratinocytes: a key driver of innate immunity and vitiligo pathogenesis.
  14. The alarmin Interleukin-33 modulates platelet proteome, function and biogenesis.
  1. Trends Biochem Sci. 2026 Mar 18. pii: S0968-0004(26)00005-8. [Epub ahead of print]
    Mitoxyperilysis: fasting-induced cell death in immunometabolism and disease.
    Radhwan Al-Zidan, Manjul Gautam, Si Ming Man.
      Recent work by Wang and colleagues reveals a unique mode of cell death called mitoxyperilysis, driven by mitochondrial proximity-dependent rupture of the plasma cell membrane. This lytic cell death is triggered by immune agonists combined with fasting or nutrient starvation, offering therapeutic implications in sepsis and cancer.
    Keywords:  NINJ1; ROS; actin cytoskeleton; cytokines; inflammation; mTOR
    DOI:  https://doi.org/10.1016/j.tibs.2026.01.005
  2. Cell Chem Biol. 2026 Mar 16. pii: S2451-9456(26)00061-9. [Epub ahead of print]
    Transcending cell death - The diverse roles of necroptosis signal adaptors in pathogen infection.
    Fangmin Huang, Jianwei Li, Francis Ka-Ming Chan.
      Necroptosis is a critical host response against pathogenic challenge. As such, many pathogens have developed strategies to fend off host cell necroptosis. This tug-of-war between the host and pathogen has led to the widely held view that necroptosis evolves primarily as a host response to infection. Paradoxically, pathogens that encode caspase inhibitors and therefore render infected cells sensitive to necroptosis also develop strategies that block necroptosis. Hence, cell death alone may not be sufficient to account for the protective role of necroptosis signal adaptors in host defense. We propose an alternative model in which cell death signal adaptors function as sensors of pathogen-encoded activities. In this scenario, pathogen interference with necroptosis may not only affect host cell death but also tune the magnitude and quality of the ensuing immune response. The crosstalk between necroptosis and other inflammatory cell death programs during viral infection will also be discussed.
    Keywords:  RIPK1; RIPK3; ZBP1; caspase 8; immune response; inflammation; virus infection
    DOI:  https://doi.org/10.1016/j.chembiol.2026.02.006
  3. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2534066123
    ATP13A2 restrains macrophage NLRP3 inflammasome activation to repress neurodegeneration via modulating mitochondrial homeostasis.
    Ziqi Zou, Jiajie Zhou, Yanhua Lu, Yuting Huang, Linru Zhou, Xiaoyu Wang, Jiahui Chen, Hengrui Tian, Xinnuo Ge, Chenyao Guo, Weiran Yao, Xiaosheng Zheng, Jia He, Yue Du, Yiting Zhou, Yinjing Song, Wei Luo, Qingqing Wang, Jun-Ping Liu, Meng Xia.
      Neuro-immune crosstalk is increasingly recognized in Parkinson's disease (PD), and ATP13A2 is well known for its neuroprotective role. However, it remains unclear whether ATP13A2 mutations carried by PD patients contribute to immune dysfunction that exacerbates disease progression. Here, we systematically demonstrate that many ATP13A2 mutations result in a loss-of-expression phenotype. ATP13A2 is highly expressed in macrophages. Myeloid ATP13A2 deficiency causes uncontrolled NLRP3 inflammasome activation driven by lysosomal alkalization and subsequent disrupted mitochondrial homeostasis, rendering mice susceptible to a PD-like phenotype. PD-linked ATP13A2 loss-of-expression mutants fail to restore the ATP13A2 levels required to suppress NLRP3 hyperactivation in ATP13A2-depleted human THP-1 monocytes. Macrophages from a PD patient carrying the ATP13A2 loss-of-expression L927P mutation exhibit excessive NLRP3 activation due to lysosomal-mitochondrial dysfunction. Our findings provide insight into PD pathogenesis, emphasizing genetic factor-driven dysregulated macrophage NLRP3 activation, particularly in ATP13A2 loss-of-expression mutation cases.
    Keywords:  ATP13A2 mutation; NLRP3 inflammasome; Parkinson’s disease; macrophage; neuroinflammation
    DOI:  https://doi.org/10.1073/pnas.2534066123
  4. EMBO J. 2026 Mar 20.
    Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
    Di Chen, Antony Fearns, Christopher J Peddie, Maximiliano G Gutierrez.
      Endomembrane damage of intracellular vesicles triggers signals that activate membrane repair in mammalian cells to restore homeostasis. However, the signals that drive diverse membrane repair recruitment at the individual organelle level are unknown. Here by recording Ca2+ leakage history with a newly developed Ca2+ probe in human macrophages, we discovered that Ca²⁺ leakage serves as a conserved signal that triggers ATG8/LC3 lipidation after different types of sterile membrane damage. The damaged compartments consisted of both single membrane and multilayered membrane structures undergoing extensive membrane remodelling. We show the complexity and acidification of these ATG8/LC3-positive compartments depends on the nature of the membrane damage trigger. Functionally, the formation of these multimembrane ATG8/LC3-positive compartments restricted membrane damage independently of canonical autophagy and the recruitment of ESCRT components CHMP2A/CHMP4B. Altogether, we show that endolysosomal Ca²⁺ leakage triggers non-canonical LC3 lipidation on damaged membranes to promote membrane repair in human macrophages.
    Keywords:  Ca2+ Leakage; Lysosome Damage; Macrophages; Membrane Repair; Non‑canonical LC3 Lipidation
    DOI:  https://doi.org/10.1038/s44318-026-00741-z
  5. Nat Immunol. 2026 Mar 18.
    Cofilin-1 is a redox-sensitive guard of the NLRP3 inflammasome.
    Yong Hwan Park, Ezgi D Batu, Brynja Matthiasardottir, YeJi Kim, Yeliz Z Akkaya-Ulum, Daniel L Kastner, Jae Jin Chae.
      Mutations in NLRP3 can cause a spectrum of the autoinflammatory cryopyrin-associated periodic syndromes (CAPS). Reactive oxygen species (ROS) have a central role in NLRP3 inflammasome activation. Here we show that cofilin-1, an actin-severing protein, is a negative regulator of the NLRP3 inflammasome. In resting cells, cofilin-1 directly bound NLRP3, but after stimulation with NLRP3 inflammasome activators, it was oxidized by ROS and dissociated from NLRP3. CAPS-associated mutant NLRP3 exhibited reduced binding to cofilin-1. Residues 101-104 of cofilin-1 were critical for NLRP3 interaction. Oxidation-independent peptides containing this NLRP3 binding motif suppressed inflammasome activation induced by endogenous CAPS-associated mutations and ex vivo NLRP3 activators such as ATP and nigericin. Bioinformatic structural analyses corroborate a model in which cofilin-1 has a pivotal function in NLRP3 activation by ROS and support the potential use of cofilin-1-derived peptides in individuals who are unresponsive to or intolerant of other forms of NLRP3 blockade.
    DOI:  https://doi.org/10.1038/s41590-026-02477-8
  6. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2523470123
    Subcellular calcium dynamics and organelle perturbations in resistosome-mediated cell death.
    Yi-Feng Chen, Kuan-Yu Lin, Ching-Yi Huang, Liang-Yu Hou, Enoch Lok Him Yuen, Wei-Che Jimmy Sun, Bing-Jen Chiang, Chin-Wen Chang, Hung-Yu Wang, Tolga Osman Bozkurt, Chih-Hang Wu.
      Plant nucleotide-binding domain leucine-rich repeat-containing (NLR) proteins act as intracellular immune receptors that assemble into resistosomes to execute immune responses. However, the subcellular processes during cell death following resistosome activation remain unclear. Here, we visualized the changes in calcium signaling and organelle behavior after activation of the NRC4 (NLR required for cell death 4) resistosome. We found that NRC4 membrane enrichment coincided with calcium influx. This is followed by sequential mitochondria and plastid disruption, endoplasmic reticulum fragmentation, and cytoskeleton depolymerization. Subsequent loss of plasma membrane integrity, nuclear shrinkage, and vacuolar collapse mark the terminal stage of cell death. Our findings reveal a spatiotemporally resolved cascade of subcellular events downstream of resistosome activation, providing mechanistic insight into the execution phase of plant immune cell death.
    Keywords:  NLR-required for cell death; calcium; hypersensitive cell death; nucleotide-binding domain leucine-rich repeat-containing protein; organelles
    DOI:  https://doi.org/10.1073/pnas.2523470123
  7. Sci Adv. 2026 Mar 20. 12(12): eadz5906
    Caspase-3/7 deficiency results in enhanced intestinal inflammation and reduced tumorigenesis.
    Wei Xie, Laura Wyckaert, Mike Vadi, Bruno Verstraeten, Tatyana Divert, Jef Haerinck, Riet De Rycke, Femke Baeke, Mohamed Lamkanfi, Geert Berx, Adam Wahida, Peter Vandenabeele.
      Aberrant intestinal epithelial cell (IEC) death is common in inflammatory bowel disease (IBD) and related animal models. While various cell death pathways contribute to disease, the dominant modalities and their regulatory mechanisms in intestinal inflammation remain ill defined. Using the DSS colitis model, we examined the contribution of apoptosis (Casp3/7ΔIEC), necroptosis (MlklΔIEC), pyroptosis (GsdmeΔIEC, Gsdmd-/-), and ferroptosis (Gpx4iΔIEC) in IECs. Mice lacking caspase-3/7 in IECs showed worsened colitis, higher mortality, and impaired regeneration, not seen in the other transgenic mice. Caspase-3/7 deficiency in IECs hindered stem cell proliferation and increased inflammatory cell death, disrupting barrier integrity and delaying recovery. Despite heightened inflammation, Casp3/7ΔIEC mice had reduced tumor formation in the AOM/DSS-induced colorectal cancer model. These findings highlight a protective role for caspase-3/7 in controlling inflammation and tissue regeneration, while promoting tumorigenesis following intestinal injury, and suggest modulation of caspase-3/7 as a promising therapeutic strategy in IBD and colorectal cancer.
    DOI:  https://doi.org/10.1126/sciadv.adz5906
  8. Cell Host Microbe. 2026 Mar 18. pii: S1931-3128(26)00083-1. [Epub ahead of print]
    Glycogen phosphorylase L confers metabolic flexibility in neutrophils to fight fungal infections in nutrient-deprived tissues.
    Wonseok Choi, De-Dong Li, Colin T McLaughlin, Doureradjou Peroumal, Kiyoshi P Shiomitsu, Gillian A Moschetta, Hossein Rahimi, Shuxia Wang, Kiaan Biswas, Danielle Xie, Charles K Vorkas, Partha S Biswas.
      Neutrophils are crucial for defense against systemic Candida albicans infections and rely on glucose for their antifungal functions, including the production of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs). In infected tissues, glucose availability is limited due to fungal consumption, posing metabolic challenges for neutrophils. We demonstrate that neutrophils overcome glucose deprivation by activating the glycogen phosphorylase liver form (PYGL) enzyme, which mobilizes intracellular glycogen stores that fuel antifungal activity. Upon C. albicans infection, fungal sensing by dectin-1 and downstream signaling through Syk and protein kinase A (PKA) kinases drive glycogenolysis in neutrophils. Neutrophil-specific deletion of PYGL in mice increases susceptibility to candidiasis, associated with defective ROS and NET generation. Treatment with a β₂-adrenergic receptor agonist, a clinically approved PYGL activator, enhances host defense in candidiasis. These findings reveal a metabolic reprogramming mechanism that supports neutrophil function in nutrient-deprived environments and identify PYGL as a potential strategy to bolster antifungal defenses.
    Keywords:  Candida albicans; glucose deprivation; glycogen; immune response; immunometabolism; invasive candidiasis; kidney; neutrophils; tissue microenvironment
    DOI:  https://doi.org/10.1016/j.chom.2026.02.015
  9. Mol Cell. 2026 Mar 19. pii: S1097-2765(26)00129-2. [Epub ahead of print]86(6): 1164-1181.e12
    ZNFX1 uses two-component ubiquitin circuitry to quarantine viral RNA.
    Daniel R Squair, Eilidh Rivers, Hanna Sowar, Arda Balci, Roosa Harmo, David J Wright, Gaurav Beniwal, Mathieu Soetens, Sunil Mathur, Aidan Tollervey, Nicola T Wood, Kuan-Chuan Pao, Callum Stanton, Adam J Fletcher, Satpal Virdee.
      The detection of viral RNA inside cells triggers a diverse range of antiviral responses, including global translation inhibition, interferon secretion, and RNA sequestration. Mutations in the gene zinc-finger NFX1-type containing 1 (ZNFX1) cause severe pediatric immunodeficiencies, including chronic viral infection and autoinflammation. Here, we show that ZNFX1 is an RNA helicase with cryptic and unusual bifurcating E3 ubiquitin ligase activity. Nucleotide-dependent RNA binding stimulates ZNFX1 to generate complex ubiquitin chains via a two-component ubiquitin circuit wired in parallel, with ubiquitin flux occurring via two competing paths. One route produces K63-linked polyubiquitin that drives RNA entrapment within self-propagating ZNFX1 aggregates, and the other route produces K48-linked polyubiquitin that drives ZNFX1 turnover. RNA entrapment restricts RNA virus replication and is reversible by deubiquitination. Pathogenic ZNFX1 variants are defective for viral restriction, linking RNA entrapment to antiviral immunity in vivo.
    Keywords:  RNA; activity-based probes; biochemistry; ubiquitin; virology
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.015
  10. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2529157123
    Atomic-level architecture and assembly mechanism of high-order structures of RIPK1 fibril revealed by integrated structural biology.
    Jing Liu, An Mu, Shaojie Ma, Yi Liu, Jing Zhang, Jun-Zhuo Zhao, Jian Wang, Xia-Lian Wu, Jun-Xia Lu.
      Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) regulates cell death pathways through RHIM domain-mediated amyloid fibril formation. While amyloid fibrils typically exist as single filaments, we identified a higher-order architecture-the mouse RIPK1 (mRIPK1) fibril network-formed by the self-assembly of mRIPK1 fibrils into quadrilateral/hexagonal lattices under slightly acidic conditions. Using an integrative approach combining solid-state NMR, transmission electron microscopy, atomic force microscopy, X-ray diffraction, Cryo-electron tomography, and molecular dynamics simulations, we elucidated the atomic structure and assembly mechanism of this network. In this study, solid-state NMR analysis demonstrates that the mRIPK1 fibril core adopts an N-shaped parallel β-sheet conformation, with dynamic regions flanking the fibril core that likely participate in network formation. We propose that the electrostatic interactions between fibril core edge residues D516-K519 or D537-K519 are essential for the network formation, with proper positioning and exposure for interaction determined by the fibril structure and the length of the dynamic flexible domain, particularly the periodic twist of the fibril. Site-directed mutagenesis confirms the critical role of these edge residues in maintaining network integrity. This study presents an atomic model of a higher-order assembly formed by naturally occurring amyloid fibrils, offers fundamental insights into hierarchical fibril assembly, and establishes a framework for designing engineered amyloid-based materials.
    Keywords:  Receptor-interacting serine/threonine-protein kinase 1 (RIPK1); amyloid fibrils; biomaterials; high-order assembly; ssNMR
    DOI:  https://doi.org/10.1073/pnas.2529157123
  11. Cell Death Differ. 2026 Mar 17.
    GEF-H1 upon microtubule destabilization drives ZBP1-dependent necroptosis.
    Xufei Zhang, Xuanheng Li, Yiyu Yang, Jie Wu, Qinjie Liu, Liting Deng, Jinjian Huang, Yun Zhao, Jianan Ren, Xiuwen Wu.
      It remains unclear for the role of microtubule-associated proteins or signaling in necroptosis. Here, we conducted high-throughput screening using a cytoskeleton compound library and identified that release of guanine nucleotide exchange factor-H1 (GEF-H1) upon microtubule destabilization triggers necroptosis. Immunoprecipitation and mass spectrometry revealed that GEF-H1 interacts with DExH-Box helicase 9 (DHX9) and protein-protein interaction network analysis indicated DHX9 is associated with necroptosis. Deficiency of either GEF-H1 or DHX9 significantly inhibits necroptosis. Mechanistically, upon microtubule destabilization, GEF-H1 is translocated to the nucleus and recruits DHX9 and RNA Pol II to the Z-DNA binding protein 1 (ZBP1) promoter region. Subsequently, increasing expression of ZBP1 drives necroptosis. In addition, GEF-H1 signaling upon microtubule destabilization also plays a positive role in lipopolysaccharide-induced cell death and inflammation. Collectively, these findings uncover an important role for GEF-H1 signaling in necroptosis and inflammation.
    DOI:  https://doi.org/10.1038/s41418-026-01711-y
  12. mBio. 2026 Mar 19. e0351925
    Caspase-mediated DDX46 cleavage unchains antiviral immunity.
    Yanfeng Liu, Zhongyuan Liu, Xiaoqing Ou, Feiyang Zhao, Jingrui Wang, Yang Qu, Xusheng Qiu, Ying Liao, Lei Tan, Cuiping Song, Chan Ding, Yingjie Sun.
      DEAD/H-box RNA helicases are critical regulators of host antiviral innate immunity. In this study, we utilized an RNA-binding protein knockout sub-library to identify DDX46, a member of the DEAD/H-box RNA helicase family, as an essential proviral host factor for RNA virus replication. While DDX46 has been shown to sequester demethylated innate immune transcripts in the nucleus and dampen interferon (IFN) production, the mechanisms underlying its regulation during viral infection remain unclear. Here, we report that RNA virus infection induces caspase-dependent cleavage of DDX46, triggering its translocation from the nucleus to the cytoplasm. This translocation unchains innate immune transcripts from nuclear retention, licensing their rapid translation and potentiating robust IFN responses. Our findings reveal a novel regulatory mechanism by which post-translational modification and subcellular relocalization of DDX46 fine-tune the host antiviral response, highlighting the functional versatility of RNA helicases in host-virus interactions.IMPORTANCEUnderstanding how host cells regulate innate immune responses to viral infection is essential for developing effective antiviral strategies. Our study uncovers a critical role for caspase-dependent cleavage and nuclear-cytoplasmic translocation of DDX46 in promoting antiviral innate immunity. These findings not only expand our knowledge of the dynamic regulation of DEAD/H-box RNA helicases during infection but also suggest that targeting the post-translational modification and localization of such helicases may offer new avenues for antiviral therapeutic development.
    Keywords:  DDX46; RNA virus; RNA-binding proteins; caspase; innate immunity
    DOI:  https://doi.org/10.1128/mbio.03519-25
  13. Cell Death Dis. 2026 Mar 18.
    Mitochondrial DNA release via VDAC1 in keratinocytes: a key driver of innate immunity and vitiligo pathogenesis.
    Jinpeng Lv, Wenhui Xu, Peiwen Jiang, Wenhao Yu, Hui Xue, Nan Hu, Yan Cao, Huansha Zhang, Chuanwei Yin, Rongyin Gao.
      Vitiligo is an autoimmune depigmenting disorder in which oxidative stress is considered a critical trigger of innate immune activation. Although keratinocytes are increasingly recognized as key contributors to disease progression, the mechanism by which they sense and propagate oxidative stress signals has remained unclear. Here, we identify mitochondrial DNA (mtDNA) release as a pivotal event linking oxidative stress to immune activation in keratinocytes. We demonstrate that hydrogen peroxide induces a sequential mitochondrial membrane remodeling process, in which mitochondrial permeability transition pore opening precedes oligomerization of the outer membrane channel protein VDAC1, enabling selective mtDNA release under non-apoptotic conditions. Escaped mtDNA acts as a danger signal that concurrently activates the cGAS-STING axis and the NLRP3 inflammasome, driving type I and type II interferon production, chemokine release, and pyroptosis. Importantly, genetic silencing or pharmacological inhibition of VDAC1 with VBIT-4 effectively blocked mtDNA release, suppressed downstream inflammatory cascades, and alleviated depigmentation and CD8⁺ T cell infiltration in a murine vitiligo model. These findings uncover a previously unrecognized mechanism by which keratinocytes transform oxidative stress into autoimmune signaling and highlight VDAC1-dependent mtDNA release as a promising therapeutic target to intercept vitiligo at an early stage.
    DOI:  https://doi.org/10.1038/s41419-026-08585-5
  14. Blood Adv. 2026 Jan 20. pii: bloodadvances.2025018363. [Epub ahead of print]
    The alarmin Interleukin-33 modulates platelet proteome, function and biogenesis.
    Lucie Gelon, Stéphane Roga, Anne Gonzalez-de-Peredo, Edith Vidal, Jean-Philippe Girard, Sonia Severin, Emma Lefrancais.
      Platelets, traditionally recognized for their involvement in hemostasis and wound healing, also play a central role in immune regulation and inflammation. Their function and production adapt in response to inflammatory cues such as cytokines and danger-associated molecular patterns. Interleukin-33 (IL-33), an alarmin released during tissue damage, particularly in lung inflammation, has been implicated in influencing platelet biology, though its exact effects remain poorly understood. To clarify IL-33's role, we examined its impact on platelet production, proteome, adhesion, secretion, and aggregation using platelets from IL-33-deficient (IL-33KO) mice and IL-33 stimulation in vivo. Our results reveal that while platelets themselves do not express IL-33, platelets isolated from IL-33KO mice display altered proteomic signatures and reduced adhesion to fibrinogen, podoplanin, and laminin, alongside impaired thrombus formation under shear stress. IL-33 administration in vivo led to proteomic remodeling characterized by increased expression of inflammatory proteins, as well as changes in platelet morphology, including increased size, typically associated with de novo production. Using lung intravital microscopy, we visualized platelet fragmentation within the lung vasculature in real time, and observed enhanced fragmentation following IL-33 stimulation. Interestingly, ST2, the receptor for IL-33, is expressed in subsets of mouse and human megakaryocytes and hematopoietic progenitors, particularly those involved in a non-canonical pathway of thrombopoiesis that enables the rapid replenishment of platelets during inflammation, infection, and aging. Together, these findings identify IL-33 as a pivotal regulator of platelet function and production, linking inflammatory signaling to the dynamic regulation of thrombopoiesis.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018363
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