bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–04–19
nineteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. Monitoring inflammasome activation by analysing ASC specks and oligomerisation.
  2. Assessing the cleavage of gasdermin-family cell death effectors by microbial proteases.
  3. Measurement of plasma membrane rupture via confocal microscopy.
  4. Bon appétit, your phagocyte.
  5. Cellular memory of sub-lethal stress.
  6. Cell death in cancer.
  7. The autoantigen TRIM21 assembles proinflammatory immune complexes after lytic cell death.
  8. Caspase-8 cleavage of p62/SQSTM1 drives TNFR-induced apoptosis.
  9. Detecting phosphorylated MLKL in murine tissues.
  10. Herpes simplex virus 1 harboring poly(T) DNA sequences as a key ligand for AIM2 inflammasome activation and host defense.
  11. Dynamic S-Acylation of GSDMA Regulates Pyroptosis.
  12. Cell death assays for the detection of acute kidney tubular necrosis.
  13. Antioxidant defenses of Francisella tularensis perturb Aim2 Inflammasome Activation.
  14. A pore-forming toxin initiates ABI1 complex switching to promote bacterial cell-to-cell spread.
  15. Methods for the detection of canonical markers of apoptosis, necroptosis and pyroptosis.
  16. DAMPs and adjuvant.
  17. Microglia detection and phagocytosis of dying neurons is regulated by CX3CR1.
  18. A bacterial CARD-NLR-like immune system controls the release of gene transfer agents.
  19. SARM1 executes neuronal parthanatos and promotes excitotoxic cell death.
  1. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00012-9. [Epub ahead of print]205 19-35
    Monitoring inflammasome activation by analysing ASC specks and oligomerisation.
    Diva Sinha, Sonia S Shah, Sharad Kumar.
      The inflammasome is a multiprotein cytosolic signalling platform that initiates inflammatory responses upon detection of microbial and danger-associated stimuli. Inflammasome assembly occurs due to the involvement of specific cytosolic pattern recognition receptors (PRRs) in response to pathogens and danger signals in host cells. This causes activation of inflammatory caspases that results in cytokine release and pyroptosis. A central player in inflammasome formation is the adaptor protein ASC (Apoptosis-associated speck-like protein containing a CARD), which bridges activated PRRs to pro-Caspase-1, leading to the formation of the inflammasome complex. This chapter provides detailed protocols for analysing inflammasome assembly by monitoring ASC speck formation using confocal microscopy and biochemically by detecting ASC oligomerisation using DSS-mediated crosslinking. Together, these methods offer complementary insights into spatial organisation and activity of inflammasomes in response to pathogens or cellular damage.
    Keywords:  ASC specks; Confocal microscopy; DSS crosslinking; Inflammasome activation; NLRP3; Oligomerisation; Pyroptosis
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.012
  2. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00008-7. [Epub ahead of print]205 37-45
    Assessing the cleavage of gasdermin-family cell death effectors by microbial proteases.
    Doris L LaRock, Christopher N LaRock.
      Gasdermin-family proteins initiate the lytic cell death program pyroptosis upon proteolytic removal of an autoinhibitory domain. For each gasdermin, proteases capable of mediating an activating cleavage event have been clearly defined. However, for new proteases, there are unique challenges in evaluating whether a specific cleavage event results in an active or inactive gasdermin. This chapter outlines methods and key controls suitable for the initial discovery and evaluation of protease activation of gasdermins that are particularly suitable for the study of alternative pathways for activation, such as by the proteases of bacteria and viruses.
    Keywords:  Cell death; Gasdermin; Proteolysis; Pyroptosis; Virulence factor
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.008
  3. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00010-5. [Epub ahead of print]205 47-62
    Measurement of plasma membrane rupture via confocal microscopy.
    Laurel B Stine, Fiachra Humphries.
      To maintain homeostasis, cells undergo a tightly regulated process called programmed cell death. Some forms of programmed cell death, such as pyroptosis, can elicit a strong inflammatory response by releasing cytokines through small protein pores. The terminal event of pyroptosis in most cells is plasma membrane rupture (PMR), which breaks down large sections of the plasma membrane and emits intracellular contents that can further amplify the inflammatory signal. In opposition to the previous dogma that PMR is a passive event, it was recently discovered that the transmembrane protein, Ninjurin-1 (NINJ1), is the key executor of PMR. Two models of NINJ1-mediated PMR predict that NINJ1 oligomerizes into filaments or ring-like structures to either open large pores or to excise sections of the membrane. Both models underpin how NINJ1 must oligomerize to execute PMR. When at rest, NINJ1 will autoinhibit oligomerization and activation by forming face-to-face dimer-dimer structures on the plasma membrane. Follow-up studies have shown that NINJ1 executes PMR for other forms of programmed cell death, including apoptosis, ferroptosis, and PANoptosis, as well as mechanical cell death. Thus, assessing NINJ1 function directly through quantification of NINJ1 oligomerization is important to expanding our understanding of both programmed and mechanistic cell death. Here, we describe methods to visualize and quantify NINJ1 oligomerization via immunofluorescence imaging of NINJ1 puncta. This protocol enables more precise and accurate measurement of NINJ1 function during PMR, surpassing conventional methods that just quantify PMR by-products.
    Keywords:  Cell death; Inflammasome; Ninjurin1; Plasma membrane rupture; Pyroptosis
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.010
  4. Cell Death Discov. 2026 Apr 14.
    Bon appétit, your phagocyte.
    Dilara C Ozkocak, Jascinta P Santavanond, Maria C Tanzer, Ivan K H Poon.
      Every day, billions of cells in the human body undergo apoptosis as part of normal tissue turnover. The swift clearance of these dying cells by phagocytes is an essential process to limit the release of intracellular contents that can disrupt tissue homeostasis and promote inflammation, autoimmunity, and chronic disease. Thus, as with the unseen yet continuous work of a well-run kitchen, effective apoptotic cell clearance sustains multicellular organisms. In cooking, ingredients must be deliberately gathered, trimmed, seasoned, cooked, and plated before becoming part of a satisfying meal. Analogously, apoptotic cells undergo an equally deliberate 'meal preparation' process in which they transform themselves to be optimally suited for consumption by professional and non-professional phagocytes. This preparation involves a coordinated suite of modifications, including the secretion of immunomodulatory factors, the internal partitioning of organelles, and the exposure of 'eat-me' signals. Additionally, maintaining membrane integrity during apoptosis can be viewed as a 'protective wrapping' that preserves 'edible' cargo while preventing the inflammatory spillover that would result from premature plasma membrane rupture (PMR). In this perspective, we highlight how these distinct, yet interconnected layers of apoptotic cell 'cooking' converge to shape and influence the eventual phagocytic encounter. A deeper understanding of how apoptotic cells prepare themselves for clearance not only reframes our view of cell death, but also offers opportunities to harness or correct these processes in pathological settings where clearance fails.
    DOI:  https://doi.org/10.1038/s41420-026-03099-7
  5. Immunity. 2026 Apr 14. pii: S1074-7613(26)00087-7. [Epub ahead of print]59(4): 801-812
    Cellular memory of sub-lethal stress.
    Stephen W G Tait, Andrew Oberst.
      Regulated cell death-processes such as apoptosis, pyroptosis, necroptosis, and ferroptosis-is essential for development, tissue homeostasis, and response to infection or cellular stress. The proteins involved in regulated cell death necessarily possess powerful and potentially damaging activities, including proteolysis, membrane pore formation, DNA cleavage, and inflammatory pathway activation. Traditionally, these activities drive cell death. However, sub-lethal activation of these pathways possesses the potential to promote sustained inflammation, senescence, or oncogenic transformation. Here, we discuss the idea that sub-lethal activation of the cell's intrinsic death programs-rather than the external stresses that initiate these programs-may represent a key mediator of long-term tissue change, with implications for chronic inflammation, aging, and tumorigenesis.
    Keywords:  aging; apoptosis; ferroptosis; inflammation; innate immunity; necroptosis; pyroptosis; senescence
    DOI:  https://doi.org/10.1016/j.immuni.2026.02.017
  6. Cell. 2026 Apr 16. pii: S0092-8674(26)00325-9. [Epub ahead of print]189(8): 2322-2356
    Cell death in cancer.
    Marcus Conrad, Andreas Strasser, Philipp J Jost, Junying Yuan, Feng Shao, Peter Vandenabeele, Adam Wahida.
      "Evasion of cell death" is a hallmark of cancer, enabling transformed cells to withstand oncogenic and therapeutic stress. Restoring cancer cell death is an appealing strategy but requires a deep understanding of cell death programs. Over the past two decades, the cell death field has expanded from apoptosis to include necroptosis, pyroptosis, ferroptosis, and other emerging programs, reshaping cancer biology and revealing therapeutic opportunities. While apoptosis remains the primary radiation- and chemotherapy-induced cell death program, non-apoptotic programs can drive inflammatory responses and orchestrate the interplay among tumor, stroma, and immune components, influencing immunotherapy outcomes. Ferroptosis, an iron-dependent, lipid peroxidation-driven cell death modality, lacks a canonical induction signal and arises from perturbations in lipid, iron, and redox metabolism. This review presents a unified framework for understanding the roles of major cell death programs in cancer development, progression, and treatment response, as well as addressing resistance to cancer cell death and immune suppression. "Our bodies are made of cells that live, and just as surely, of cells that must die." -S. Brenner.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.024
  7. Sci Immunol. 2026 Apr 17. 11(118): eads9680
    The autoantigen TRIM21 assembles proinflammatory immune complexes after lytic cell death.
    Esther L Jones Evans, Benjamin Demarco, Han Cai, Madelon M E de Jong, Sarah Hill, Marcus A Widdess, Joannah R Fergusson, Ryan E Glass, Gemma Harris, Gracie J Mead, Yavuz F Yazicioglu, Saba Nayar, Benjamin A Fisher, Mark S Cragg, Alexander J Clarke, Audrey Gérard, Jelena S Bezbradica, Lynn B Dustin.
      Sjögren's disease (SjD) causes localized and systemic inflammation and autoantibody production against intracellular proteins such as TRIM21/Ro52 (tripartite motif-containing protein 21). TRIM21, an E3 ubiquitin ligase, binds antibody Fc domains on opsonized pathogens that have escaped extracellular immunity and entered the cytosol. TRIM21 then ubiquitinates these pathogens, driving their proteasomal degradation. How TRIM21 becomes an autoantigen remains unclear. We show that TRIM21 is released upon lytic cell death (pyroptosis or necroptosis) but not apoptosis. Although many cytosolic proteins are released by dead cells, liberated TRIM21 is distinct: Its high antibody affinity enables binding to Fc domains of circulating immunoglobulins, forming large immune complexes (ICs). These ICs increase in SjD, where anti-TRIM21 autoantibodies interact with released TRIM21 via Fc and F(ab')2. TRIM21 ICs are taken up by macrophages, which drive proinflammatory responses, antigen presentation, and metabolic changes in high interferon environments. Thus, TRIM21 may perpetuate inflammation and autoantigen presentation, resulting in high immunogenicity.
    DOI:  https://doi.org/10.1126/sciimmunol.ads9680
  8. Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00191-7. [Epub ahead of print]86(8): 1419-1421
    Caspase-8 cleavage of p62/SQSTM1 drives TNFR-induced apoptosis.
    Monica Nanni, Jayanta Debnath.
      In this issue of Molecular Cell, Nössing et al.1 demonstrate that TNF activates a species-specific cleavage of p62/SQSTM1 by caspase-8, which activates extrinsic apoptosis via a feedforward loop. Introducing this missing p62 cleavage site into mice amplifies TNF-driven inflammation, shock, and mortality.
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.015
  9. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00009-9. [Epub ahead of print]205 159-170
    Detecting phosphorylated MLKL in murine tissues.
    Riley M Williams, Bikash Thapa, Siddharth Balachandran.
      The programmed cell death process of necroptosis is activated when Receptor Interacting protein Kinase (RIPK)3 phosphorylates its substrate Mixed Lineage Kinase Like protein (MLKL). Phosphorylated MLKL oligomers then traffic to cellular membranes, including the plasma membrane, and perforate these membranes. MLKL-driven pore formation in the plasma membrane alters the cell osmolarity, causing it to swell and undergo necrotic death. Phosphorylation of MLKL by RIPK3 is essential for the execution of necroptosis, and is thus a widely accepted biomarker for this mode of cell death. In this chapter, we describe our procedure for detecting phosphorylated murine MLKL in influenza A virus (IAV) infected lung tissues, and within tumors following treatment with the compound CBL0137.
    Keywords:  CBL0137; Influenza A virus; MLKL; Necroptosis; RIPK3; Z-DNA; Z-RNA; ZBP1
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.009
  10. Nat Commun. 2026 Apr 13.
    Herpes simplex virus 1 harboring poly(T) DNA sequences as a key ligand for AIM2 inflammasome activation and host defense.
    SuHyeon Oh, Jueun Oh, Kyeongchan Im, Tae Hyoung Kim, Jihye Lee, Kihye Shin, Nabukenya Mariam, Cheong Seok, Jaewoo Park, GyeongJu Yu, Hayeon Kim, Suhyun Kim, Seyun Shin, Jinwoo Gil, Sehee Park, Yoon-Seok Chung, Daesik Kim, Young Ki Choi, Eui Tae Kim, Joo Sang Lee, SangJoon Lee.
      Herpes simplex virus type 1 (HSV-1) infection remains a major global health challenge, yet the mechanisms underlying strain-specific innate immune responses are poorly understood. Here, we show that distinct HSV-1 strains differentially activate the absent in melanoma 2 (AIM2) inflammasome. The HF strain robustly induces AIM2-dependent inflammasome activation, whereas the F and KOS strains elicit minimal responses despite comparable infection efficiency. We demonstrate that this difference is driven by viral genomic features rather than replication capacity. Genomic analyses identify a poly(T) DNA sequence within the UL25-UL26 intergenic region that is enriched in the HF strain. Deletion of a 14-mer poly(T) sequence markedly impairs inflammasome activation, cytokine release, and host protection in vivo, whereas introduction of a poly(T) tract into the F strain is sufficient to confer AIM2 activation and enhanced host defense. Furthermore, poly(T)-mediated AIM2 activation is length-dependent, conserved in human macrophages, and requires a cGAS-STING-IRF1 licensing axis. Together, these findings identify viral poly(T) DNA as a key determinant of strain-specific AIM2 inflammasome activation and reveal how viral genomic variation shapes innate immune recognition.
    DOI:  https://doi.org/10.1038/s41467-026-71896-w
  11. ACS Chem Biol. 2026 Apr 13.
    Dynamic S-Acylation of GSDMA Regulates Pyroptosis.
    Zhipeng Tao, Ritesh P Thakare, Melyssa Cheung, Jianan Zhang, Xin Chen, Xiaodi Hu, Brian G Pierce, Xu Wu, Junhao Mao.
      GSDMA, the primary member of the gasdermin family found in the skin, is critical for pathogen-induced pyroptosis during infection. Recent studies revealed that another gasdermin, GSDMD, undergoes palmitoylation during pyroptosis. However, whether and how the other gasdermin members undergo lipid modification remain poorly understood. Here, we demonstrate that GSDMA is S-acylated at the conserved cysteine residues in its N-terminal domain. We show that the S-acylation of GSDMA promotes pyroptosis by facilitating its membrane anchoring and protein oligomerization, a mechanism distinct from the palmitoylation of GSDMD at the N-terminal C191 residue. In addition, we present evidence that recombinant proteins of GSDMA and GSDMD can undergo S-acylation in vitro independent of palmitoyl transferases via direct interaction with palmitoyl-CoA. Furthermore, we identify ABHD17A as one of the deacylating enzymes that regulate the dynamic fatty acylation cycle of GSDMA. Overall, our studies reveal new molecular mechanisms underlying GSDMA function through S-acylation and underscore its important role in regulating pyroptosis mediated by GSDMA.
    DOI:  https://doi.org/10.1021/acschembio.5c00050
  12. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00016-6. [Epub ahead of print]205 125-140
    Cell death assays for the detection of acute kidney tubular necrosis.
    Francesca Maremonti, Andreas Linkermann.
      Acute tubular necrosis (ATN) is a central driver of nephron loss and progression to kidney failure. Dissecting the cellular pathways that govern tubular necrosis requires reliable systems to model and quantify cell death. This chapter introduces methodologies for isolating murine renal tubules ex vivo and describes a panel of assays-including biochemical, molecular, and imaging approaches-that enable the detection of regulated necrosis in kidney tubules. We provide theoretical background, practical workflows, examples of applications.
    Keywords:  Acute kidney injury; Acute tubular necrosis; Ferroptosis; Kidney tubules; LDH; Live-cell imaging; Primary tubular cells; Regulated necrosis; Western blot; ex vivo
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.016
  13. bioRxiv. 2026 Apr 11. pii: 2026.04.09.717616. [Epub ahead of print]
    Antioxidant defenses of Francisella tularensis perturb Aim2 Inflammasome Activation.
    Zhuo Ma, Jacob Miller, Kayla Fantone, Chandra Shekhar Bakshi, Meenakshi Malik.
      Francisella tularensis is a Gram-negative bacterium that causes tularemia, a fatal zoonotic disease. F. tularensis has been used in the bioweapon programs of several countries. Its potential use as a bioterrorism agent led the CDC to classify F. tularensis as a Tier 1 Select Agent. The cytosolic sensor absent in melanoma 2 (Aim2) detects double-stranded DNA in the cytosol of infected cells and subsequently assembles a multiprotein complex known as the inflammasome. Inflammasome activation drives the secretion of IL-1β and IL-18, key proinflammatory cytokines required for controlling F. tularensis infection. Prior studies have shown that F. tularensis actively suppresses Aim2 inflammasome activation; however, the underlying mechanism remains unknown. We hypothesized that F. tularensis suppresses Aim2-mediated responses by modulating the intracellular redox environment. We utilized an F. tularensis mutant lacking OxyR (Δ oxyR ), a transcriptional regulator that controls the expression of major antioxidant enzymes. Our results show that macrophages infected with the Δ oxyR mutant exhibit significantly higher levels of Aim2-dependent Caspase-1 and IL-1β than those infected with wild-type bacteria. The expression of interferon regulatory factor 1 and the guanylate-binding proteins GBP2 and GBP5, upstream signaling components of the Aim2 inflammasome, is markedly higher in Δ oxyR -infected macrophages than in controls. These changes were absent in Δ oxyR -infected NADPH oxidase-deficient macrophages, which are unable to generate reactive oxygen species. Collectively, these findings demonstrate that macrophage redox environment plays a key role in activating signaling components required for Aim2 inflammasome activation. This work advances our understanding of how F. tularensis -encoded factors subvert host innate immune defenses.
    DOI:  https://doi.org/10.64898/2026.04.09.717616
  14. Nat Commun. 2026 Apr 13.
    A pore-forming toxin initiates ABI1 complex switching to promote bacterial cell-to-cell spread.
    He Sun, Arlon Wizzard, John H Brumell, Darren E Higgins.
      Listeria monocytogenes (Lm), a prototypical intracellular bacterial pathogen, expresses ActA to initiate ARP2/3-mediated actin-based motility in the cytosol of host cells. Motile bacteria generate Lm-containing protrusions at the cell surface, facilitating direct cell-to-cell spread and dissemination within the host. Protrusion formation is an active, spatially regulated process, yet how Lm coordinates bacterial and host factors to orchestrate this process remains unclear. Here, we identify Abelson-interactor 1 (ABI1) as a host factor required for efficient Lm protrusion formation and cell-to-cell spread. Conditional knockout of Abi1 in mice significantly reduces susceptibility to Lm infection, while deletion of actA abrogates the protective effect of Abi1 knockout. During Lm infection, ABI1 is uncoupled from spectrin at the cell cortex and binds to EPS8 within protrusions. This ABI1 "complex switching" is initiated by the pore-forming toxin LLO, which perforates the host plasma membrane and triggers Ca2+ influx, leading to calpain-mediated cleavage of the spectrin cytoskeleton. Spectrin cleavage mobilizes ABI1, allowing ABI1 to bind EPS8 and activate EPS8's actin capping activity to facilitate local actin recycling necessary for efficient protrusion elongation and cell-to-cell spread. These findings reveal an unrecognized host-pathogen interaction, in which a bacterial pore-forming toxin induces spatially confined cytoskeletal remodeling to promote cell-to-cell spread.
    DOI:  https://doi.org/10.1038/s41467-026-71510-z
  15. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00014-2. [Epub ahead of print]205 171-187
    Methods for the detection of canonical markers of apoptosis, necroptosis and pyroptosis.
    Yuanxin Yang, Daichao Xu.
      Programmed cell death (PCD) represents an essential biological mechanism for preserving tissue homeostasis and removing compromised cells. The most extensively characterized forms of programmed cell death - apoptosis, pyroptosis, and necroptosis - are each initiated through unique signaling mechanisms, encompassing TNF-TNFR1 signaling, Toll-like receptor activation, interferon-mediated responses, along with both the canonical NLRP3-GSDMD and non-canonical Caspase-11-GSDMD pyroptotic pathways. In this protocol, we systematically review combinatorial pharmacological strategies employing small-molecule drugs and cognate ligands to selectively induce specific PCD modalities, with parallel discussion of established detection platforms for monitoring cell death progression.
    Keywords:  Apoptosis; Necroptosis; Pyroptosis
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.014
  16. Curr Opin Virol. 2026 Apr 14. pii: S1879-6257(26)00023-4. [Epub ahead of print]76 101531
    DAMPs and adjuvant.
    Minami Kojima, Daisuke Ori, Taro Kawai.
      Vaccine adjuvants are increasingly recognized to modulate immune responses not through single pattern-recognition receptors, but through broader cellular stress responses that lead to innate immune activation. Damage-associated molecular patterns (DAMPs) play a central role in linking adjuvant-induced cellular perturbations to downstream immune signaling. In this review, we summarize current understanding of how cellular stress and cell death associated with adjuvant administration result in the release of DAMPs, and how these signals are sensed by major innate immune pathways, including Toll-like receptors, cytosolic DNA sensing via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, and NLR family pyrin domain containing 3 (NLRP3) inflammasomes. We further discuss the role of DAMP-mediated signaling in dendritic cell activation and the subsequent regulation of adaptive immune responses. Finally, we introduce chitosan-based adjuvants as an example of materials that induce innate immune activation through DAMP-associated pathways, and discuss their implications for the rational design of future vaccine adjuvants.
    DOI:  https://doi.org/10.1016/j.coviro.2026.101531
  17. bioRxiv. 2026 Apr 06. pii: 2026.04.02.716180. [Epub ahead of print]
    Microglia detection and phagocytosis of dying neurons is regulated by CX3CR1.
    Maryanne N Barasa, Alicia N Pietramale, Robert A Hill.
      Neuronal cell death is a hallmark of many neurodegenerative diseases. Effective detection and clearance of cell debris generated during cell death events is essential to prevent a degenerative cascade. Brain resident microglia are responsible for performing these functions through complex cell-cell signaling involving both "find-me" and "eat-me" cues. To examine microglial responses to neuronal cell death in vivo, we investigated neuron/microglia CX3CL1/CX3CR1 signaling using intravital optical imaging in mouse cortex and a single-cell ablation technique called 2Phatal. We find that CX3CL1 aggregates as puncta on microglia and that this pattern is maintained when microglia engulf dying neurons. Additionally, disruption of this signaling via Cx3cr1 deletion when both few and many neurons are dying leads to delayed cell corpse clearance, partly due to a delay in microglial engagement with the dying cells. Overall, our work uncovers a precise role for CX3CL1/CX3CR1 signaling in regulating the microglial response to dying neocortical neurons.
    DOI:  https://doi.org/10.64898/2026.04.02.716180
  18. Nat Microbiol. 2026 Apr 16.
    A bacterial CARD-NLR-like immune system controls the release of gene transfer agents.
    Emma J Banks, Pavol Bárdy, Ngat T Tran, Phuong M Nguyen, Boris Stojilković, Kevin Gozzi, Abbas Maqbool, Tung B K Le.
      Bacteria use immune systems to detect and defend against mobile genetic elements including phages. Gene transfer agents (GTAs) are domesticated prophages with phage-like characteristics including the ability to induce host cell lysis for gene transfer. Whether GTAs elicit or avoid bacterial immune systems is poorly understood. Here, a transposon mutagenesis with deep sequencing screen in Caulobacter crescentus identified a tripartite system, LypABC, essential for GTA-mediated cell lysis and gene transfer. LypABC resembles a caspase recruitment domain-nucleotide-binding leucine-rich repeat (CARD-NLR) anti-phage defence system. LypABC is dispensable for DNA packaging into GTA particles but required for host cell lysis, involving the peptidase domains of LypA and LypC, and the ATPase domain of LypB. As LypABC overproduction is toxic, strict regulation through the transcriptional repressor CdxB is required. CdxB binds the promoters of lypABC and of essential GTA activator genes, coupling GTA activation to host cell lysis. Our findings suggest that bacterial immune systems can be co-opted to support horizontal gene transfer by GTAs.
    DOI:  https://doi.org/10.1038/s41564-026-02316-4
  19. Neuron. 2026 Apr 16. pii: S0896-6273(26)00218-7. [Epub ahead of print]
    SARM1 executes neuronal parthanatos and promotes excitotoxic cell death.
    Tong Wu, Liya Yuan, Yo Sasaki, Si Jia Chen, William Buchser, A Joseph Bloom, Aaron DiAntonio, Jeffrey Milbrandt.
      The nicotinamide adenine dinucleotide (NAD+) hydrolase sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is the central executioner of pathological axon degeneration and is allosterically activated by an increased nicotinamide mononucleotide (NMN)/NAD+ ratio. DNA damage induces NAD+ loss and an increased NMN/NAD+ ratio by hyperactivating poly(ADP-ribose) polymerase 1 (PARP1), which triggers the parthanatos cell death pathway. Multiple mechanistically distinct DNA-damaging agents activate SARM1 and induce axon degeneration following PARP1 activation. Remarkably, SARM1 is required for key steps downstream of hyperactivated PARP1, which are pathognomonic of parthanatos, including mitochondrial depolarization, nuclear translocation of apoptosis-inducing factor (AIF), and cell death. Hence, SARM1 is an essential component of neuronal parthanatos. Moreover, complex neurodegenerative stimuli whose mechanisms include activation of parthanatos, such as 1-methyl-4-phenyl-pyridinium (MPP+) dopaminergic neuron toxicity and N-methyl-D-aspartate (NMDA) excitotoxicity, are potently protected by SARM1 inhibition. These findings place SARM1 at the nexus of multiple mechanisms driving neuronal cell death, thereby greatly expanding the potential clinical utility of SARM1 inhibitors beyond diseases of axon loss.
    Keywords:  ALS; NAD⁺ metabolism; Parkinson’s disease; SARM1; dopaminergic neurons; excitotoxicity; iPSC; neurodegeneration; parthanatos; stroke
    DOI:  https://doi.org/10.1016/j.neuron.2026.03.027
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