bims-cediti 2026-03-29 papers

bims-cediti

Biomed News

on Cell death in innate immunity, inflammation, and tissue repair

Issue of 2026–03–29
eighteen papers selected by
Kateryna Shkarina, Universität Bonn

Perturbation of azurophilic granule integrity drives NLRP3-independent IL-1β processing and release in neutrophils.
NLRP1B is an integrated decoy that subverts Shigella flexneri E3 ligase activity to promote effector-triggered immunity.
Adaptor protein supersaturation drives innate immune signaling and cell fate.
Diverse Scaffolds Facilitate NLRP3 Clustering and Inflammasome Formation in Response to Perturbations in Cell Homeostasis.
Autoinhibitory control of MLKL governs pseudokinase domain phosphorylation and oligomerization during necroptosis.
GTPase Rab11b and effector Rab11-FIP2 promote NLRP3 stability during inflammasome priming.
Deubiquitinating enzyme MINDY2 regulates TNF-α-induced cell death by targeting RIPK1.
Salmonella Typhi asparaginase-dependent activation of GCN2 promotes bacterial killing in murine macrophages.
DNA-triggered AIM2 condensation orchestrates immune activation and regulation.
The Open Reading Frame 7b of the SARS-CoV-2 Disperse Trans-Golgi and Activate the NLRP3 Inflammasome.
Human NLRP3 inflammasome activation leads to formation of condensate at the microtubule organizing center.
Sensing of double-stranded RNA in human cells: molecular mechanisms and cellular consequences.
Cytosol-dwelling bacteria engage in a ubiquitination race to avoid antibacterial autophagy.
DNA-PK interacts with cyclic dinucleotides and inhibits type I interferon responses.
Salmonella Enteritidis SpaO protein regulating inflammasome activation in macrophage.
Too much of a good thing: Promotion of tumor progression and metastasis by apoptotic cells.
Liquid-liquid phase separation mediated immune evasion of respiratory syncytial virus against oligoadenylate synthetase-RNase L pathway.
AMPK as a regulatory node in cell death.

J Immunol. 2026 Mar 17. pii: vkag033. [Epub ahead of print]215(3):

Perturbation of azurophilic granule integrity drives NLRP3-independent IL-1β processing and release in neutrophils.

Brandon A Miller, Katherine Horan, Derek W Abbott, Eric Pearlman, George R Dubyak.

  Interleukin 1-beta (IL-1β) is an inflammatory cytokine produced by myeloid cells in response to infection or sterile tissue damage. Secretion of bioactive IL-1β from macrophages (Mφ) or dendritic cells (DC) downstream of activated NLRP3/caspase-1 inflammasomes is the best characterized model; this is mediated by caspase-1 cleavage of proIL-1β and Gasdermin D. Gasdermin D pores that form in the plasma membrane mediate IL-1β release and pyroptotic cell death. NLRP3 inflammasome assembly is triggered by perturbation of ionic, metabolic or organelle homeostasis via diverse stimuli. A recent report demonstrated that NLRP3 activators in Mφ/DC include tyrosine kinase inhibitors such as imatinib mesylate used as frontline chemotherapeutics for chronic myelogenous leukemia (CML). This action of imatinib was initiated by lysosomal membrane permeabilization (LMP). As CML is characterized by high numbers of circulating immature granulocytes and neutrophils, we assessed the effects of imatinib on NLRP3 inflammasome signaling in murine and human neutrophils. We report that imatinib-treated neutrophils can process and release IL-1β independently of NLRP3 inflammasome assembly and the expression/activity of caspase-1 or Gasdermin D. Mechanistically, imatinib induces azurophilic granule permeabilization to drive robust cytosolic accumulation of granule-derived neutral serine proteases, serine protease-mediated processing of proIL-1β, and release of mature IL-1β. Together these findings elucidate a novel mechanism by which disruption of neutrophil granules can bypass the NLRP3 inflammasome pathway to drive serine protease-mediated IL-1β processing and release.

Keywords:  cytokines; cytotoxicity; inflammation; neutrophils; signal transduction

DOI:  https://doi.org/10.1093/jimmun/vkag033
Proc Natl Acad Sci U S A. 2026 Mar 31. 123(13): e2514645123

NLRP1B is an integrated decoy that subverts Shigella flexneri E3 ligase activity to promote effector-triggered immunity.

Siwon Chung, Hannah Hudson, Kaitlin A Stromberg, Andrew Sandstrom.

  Inflammasomes are cytosolic immune complexes that recognize pathogen-associated stimuli to initiate a potent inflammatory response. While some inflammasomes directly recognize pathogen-associated molecules, others, such as the NLRP1B inflammasome, respond to pathogen-associated activities. Specifically, the NLRP1B inflammasome senses the enzymatic activity of pathogen-secreted proteases and E3 ligases through a mechanism of "functional degradation"-effectors that promote the proteasomal degradation of NLRP1B induce activation of this inflammasome. However, why pathogens would target NLRP1B for degradation when doing so promotes a robust inflammatory response is unclear. We propose that NLRP1 acts as an integrated decoy receptor by mimicking other host proteins targeted for degradation by pathogens. Specifically, we hypothesize that NLRP1B encodes sequences and features such that these pathogen effectors are unable to distinguish between NLRP1B and their other targets. To test this hypothesis, we determine how the Shigella flexneri E3 ligase IpaH7.8 is recognized by NLRP1B and whether these interactions are equivalent to those between IpaH7.8 and its other substrates, the Gasdermin (GSDM) family of proteins. Here, we show that IpaH7.8 recognizes both the GSDMs and NLRP1B through a single shared interface and that NLRP1B presents a surface similar to that recognized by IpaH7.8 on the GSDMs. In this way, NLRP1B acts as a decoy for the GSDMs to subvert the activity of IpaH7.8 to promote inflammasome activation. These data demonstrate that NLRP1B acts as an integrated decoy receptor and establish the use of integrated decoy receptors by the vertebrate immune system.

Keywords:  NLRP1; effector-triggered immunity; inflammasome; innate immunity

DOI:  https://doi.org/10.1073/pnas.2514645123
Elife. 2026 Mar 24. pii: RP107962. [Epub ahead of print]14

Adaptor protein supersaturation drives innate immune signaling and cell fate.

Alejandro Rodriguez Gama, Tayla Miller, Shriram Venkatesan, Jeffrey J Lange, Jianzheng Wu, Xiaoqing Song, William D Bradford, Malcolm Cook, Jay R Unruh, Randal Halfmann.

  How minute pathogenic signals trigger decisive immune responses is a fundamental question in biology. Classical signaling often relies on ATP-driven enzymatic cascades, but innate immunity frequently employs death fold domain (DFD) self-assembly. The energetic basis of this assembly is unknown. Here, we show that specific DFDs function as energy reservoirs through metastable supersaturation. Characterizing all 109 human DFDs, we identified sequence-encoded nucleation barriers specifically in the central adaptors of inflammatory signalosomes, allowing them to accumulate far above their saturation concentration while remaining soluble and poised for activation. We demonstrate that the inflammasome adaptor ASC is constitutively supersaturated in vivo, retaining energy that powers on-demand cell death. Swapping a non-supersaturable DFD in the apoptosome with a supersaturable one sensitized cells to sublethal stimuli. Mapping all DFD nucleating interactions revealed that supersaturated adaptors are triggered to polymerize specifically by other DFDs in their respective pathways, limiting potentially deleterious crosstalk. Across human cell types, adaptor supersaturation strongly correlates with cell turnover, implicating this thermodynamic principle in the trade-off between immunity and longevity. Profiling homologues from fish and sponge, we find nucleation barriers to be conserved across metazoa. These findings reveal DFD adaptors as biological phase change materials in thermal batteries to power cellular life-or-death decisions on demand.

Keywords:  S. cerevisiae; immunology; inflammation; innate immunity; molecular biophysics; nucleation barrier; programmed cell death; signalosome; structural biology; supersaturation

DOI:  https://doi.org/10.7554/eLife.107962
Bioessays. 2026 Mar;48(3): e70130

Diverse Scaffolds Facilitate NLRP3 Clustering and Inflammasome Formation in Response to Perturbations in Cell Homeostasis.

Elvira Boršić-Mlinarič, Iva Hafner-Bratkovič.

A central component of innate immunity, the NLRP3 inflammasome is a multiprotein complex formed in response to a chemically and morphologically diverse spectrum of stimuli. Despite extensive investigation, no single ligand or signal has emerged to account for this breadth of activation. Here, we review the landscape of NLRP3 activation across subcellular compartments and examine how this process is shaped by a network of interacting partners. Recent studies suggest that NLRP3 responds to cellular perturbations, such as changes in lipid membrane composition, protein localization, or organelle function. We propose that distinct upstream cues converge to generate diverse molecular scaffolds that recruit NLRP3. The NLRP3-scaffold interactions promote NLRP3 clustering, destabilize its autoinhibited conformation, and drive assembly of the inflammasome. NLRP3 is thus an adaptable sensor, equipped with versatile molecular interactions that allow it to integrate multiple danger signals into inflammasome activation.

DOI: https://doi.org/10.1002/bies.70130
Cell Rep. 2026 Mar 20. pii: S2211-1247(26)00208-1. [Epub ahead of print]45(4): 117130

Autoinhibitory control of MLKL governs pseudokinase domain phosphorylation and oligomerization during necroptosis.

Michelle J Pan, Derek W Abbott.

  Necroptotic cell death triggers the release of inflammatory mediators but the exact mechanisms controlling its activation are not fully understood. Previous studies have identified key steps during necroptosis, which are believed to be coupled: MLKL phosphorylation by RIPK3, release of N-terminal autoinhibition, and MLKL oligomerization. Yet, ectopic expression of phosphomimetic MLKL is insufficient to induce necroptosis in human cells. Here, we employ five different pharmacological, biological, and genetic methods to demonstrate that inhibiting the MLKL N terminus prevents both phosphorylation and oligomerization. Conversely, loss of interaction between the N-terminal four-helical bundle and brace domains demonstrates basal MLKL phosphorylation, even in the absence of necroptotic stimuli. Moreover, we show that MLKL phosphorylation is not necessary for maintaining MLKL oligomer stability. We propose that MLKL is released from autoinhibition prior to phosphorylation, explaining why phosphomimetic MLKL lacks cytotoxic activity.

Keywords:  CP: immunology; MLKL; RIPK1; RIPK3; autoinhibition; cell death; cytotoxicity; kinase; necroptosis; oligomerization; pseudokinase

DOI:  https://doi.org/10.1016/j.celrep.2026.117130
EMBO J. 2026 Mar 25.

GTPase Rab11b and effector Rab11-FIP2 promote NLRP3 stability during inflammasome priming.

Caroline S Gravastrand, Maria Yurchenko, Stine Kristensen, Astrid Skjesol, Carmen Chen, Sindre Ullmann, Zunaira Iqbal, Karoline Ruud Dahlen, Kashif Rasheed, Unni Nonstad, Liv Ryan, Terje Espevik, Harald Husebye.

  Membrane trafficking through the trans-Golgi network has been shown to guide activation of the NLRP3 inflammasome. Rab11 GTPases and their effector Rab11-FIP2 regulate endosomal trafficking and retrograde transport. Here, we demonstrate that Rab11b and Rab11-FIP2 contribute to NLRP3 and pro-IL-1β stabilization during the inflammasome priming phase, which is followed by inflammasome activation. We show Rab11-FIP2 to promote TAK1 phosphorylation and TAK1-mediated activation of IKKβ, a process controlling NLRP3 translocation to the trans-Golgi network. Human NLRP3 and Rab11-FIP2 bind each other via their phosphatidylinositol-4 phosphate (PI4P)-binding domains KMKK and N-terminal C2 domain, respectively. We also provide evidence indicating that Rab11-FIP2 stabilizes NLRP3 on early endosomes, which is important for ASC speck formation. These findings provide insights into the mechanisms controlling stability and intracellular trafficking of NLRP3 in human macrophages.

Keywords:  Early Endosome; Inflammasome Activation; LPS Priming; NLRP3 Stability; Rab11-FIP2

DOI:  https://doi.org/10.1038/s44318-026-00755-7
Cell Rep. 2026 Mar 20. pii: S2211-1247(26)00212-3. [Epub ahead of print]45(4): 117134

Deubiquitinating enzyme MINDY2 regulates TNF-α-induced cell death by targeting RIPK1.

Wenyang Huang, Yushi Chen, Danni Chen, Yuanyuan Liu, Jiaqin Lu, Jianting Feng, Juan Lin, Lisheng Li.

  Ubiquitination plays a crucial role in the tumor necrosis factor (TNF)-α signaling pathway. To identify mechanisms by which ubiquitination regulates TNF-α signaling, we perform a screen using a gene expression library of ubiquitination-modifying enzymes. We find that the deubiquitinating enzyme MINDY2 inhibits TNF-α-induced cell death. MINDY2 modulates ubiquitination at the K612 site of RIPK1, which in turn attenuates RIPK1 recruitment by TNFR1, thereby influencing the complex 1 signaling pathway and RIPK1-dependent cell death. To investigate the in vivo function of MINDY2, we generate MINDY2-knockout mice. Compared to wild-type mice, MINDY2-deficient mice exhibit more severe hypothermia, mortality, and intestinal damage after TNF-α challenge. Collectively, our work reveals that MINDY2 is a checkpoint in RIPK1-dependent cell death, and that its deficiency exacerbates TNF-mediated tissue damage in vivo.

Keywords:  CP: Immunology; MINDY2; RIPK1; TNF-α; necroptosis; ubiquitination

DOI:  https://doi.org/10.1016/j.celrep.2026.117134
bioRxiv. 2026 Mar 17. pii: 2026.03.16.712107. [Epub ahead of print]

Salmonella Typhi asparaginase-dependent activation of GCN2 promotes bacterial killing in murine macrophages.

Zachary Powers, Michael McFadden, Gi Young Lee, Tracey L Schultz, Luiza Castro Jorge, Daniel Edwards, Simon Sanchez-Paiva, Jonathan Sexton, Katherine R Spindler, Jeongmin Song, Mary X O'Riordan.

Many intracellular pathogens stimulate host cell stress by directly or indirectly causing an imbalance in host nutrients; depletion of amino acid pools in particular can act as a danger signal to infected cells. Using a restrictive host model of Salmonella enterica serovar Typhi (S. Typhi) infection, we identify early induction the integrated stress response (ISR) by viable bacteria, but not heat-killed bacteria. Genetic deletion of the amino acid sensing ISR kinase GCN2 (also known as EIF2AK4) prevented early ISR activation during S. Typhi infection, and murine macrophages lacking GCN2 show impaired bacterial clearance and decreased cytokine output. Supplementation of wildtype C57BL/6 murine macrophages with only the non-essential amino acid asparagine was sufficient to suppress S. Typhi-induced ISR activation and deletion of S. Typhi ansB, encoding an asparaginase, prevented ISR activation during infection. Pharmacological inhibition of mammalian target of rapamycin (mTOR), the other major amino acid sensing pathway in eukaryotic cells, prevented GCN2 activation and ISR induction in murine macrophages, indicating an upstream role for mTOR in signaling to GCN2. These findings suggest a role for the ISR in macrophage innate immune responses to S. Typhi infection and highlight a potential difference in nutrient-dependent signaling between the S. Typhi-susceptible human host and the restrictive murine host centered around asparagine, mTOR, and GCN2.

DOI: https://doi.org/10.64898/2026.03.16.712107
Protein Cell. 2026 Mar 25. pii: pwag024. [Epub ahead of print]

DNA-triggered AIM2 condensation orchestrates immune activation and regulation.

Quanjin Li, Xiaohan Geng, Huiwen Yan, Zhaolong Li, Miao Shi, Ziqi Zhu, Tongxin Niu, Chunqiu Zhao, Kaile Shu, Yina Gao, Han Feng, Songqing Liu, Qiuyao Jiang, Pengcheng Bu, Dong Li, Pu Gao.

The innate immune sensor AIM2 detects cytosolic DNA and initiates inflammatory responses, yet its activation mechanism remains incompletely understood. Here, we show that AIM2 undergoes liquid-liquid phase separation upon DNA binding, forming dynamic condensates both in vitro and in cells. These condensates serve as platforms for inflammasome and PANoptosome assembly, promoting immune activation across multiple pathways. Direct structural determination from condensates reveals the assembly of active-form ASC filaments. Mechanistically, liquid-phase condensation is governed by multivalent interactions involving different AIM2 domains, including previously uncharacterized regions and species-specific elements. In vitro and in vivo assays show that mutants specifically disrupting condensation impair immune complex assembly, cell death initiation, antimicrobial defense, and intestinal homeostasis. Moreover, AIM2-DNA condensates function as regulatory hubs targeted by host- and pathogen-derived factors to balance immune homeostasis or facilitate immune evasion. These findings establish liquid-phase condensation as a fundamental mechanism of AIM2 activation and a potential therapeutic target.

DOI: https://doi.org/10.1093/procel/pwag024
J Med Virol. 2026 Apr;98(4): e70894

The Open Reading Frame 7b of the SARS-CoV-2 Disperse Trans-Golgi and Activate the NLRP3 Inflammasome.

Julio García-Villalba, Laura Hurtado-Navarro, Diego Angosto-Bazarra, Alberto Baroja-Mazo, Pablo Pelegrin.

  Inflammasomes orchestrate the inflammatory response against bacterial and viral infections, thereby initiating the synthesis of pro-inflammatory cytokines, mainly IL-1β and IL-18. SARS-CoV-2 infection induces an inflammatory response mediated by the activation of NLRP1 and NLRP3 inflammasomes. In this study, we demonstrated that the open reading frame 7b (ORF7b) accessory protein of SARS-CoV-2 induces the NLRP3 inflammasome in a recombinant HEK293T model. This resulted in an increase in the distribution of NLRP3 puncta, ASC-specking cells, and caspase-1 activation. ORF7b expression also induced the dispersion of the trans-Golgi network, a well-known step in the activation of the NLRP3 inflammasome. This study proposes a novel additional mechanism by which SARS-CoV-2 promotes NLRP3 inflammasome activation by ORF7b.

Keywords:  ASC speck; COVID‐19; IL‐1; NLRP3; SARS‐CoV‐2; inflammation

DOI:  https://doi.org/10.1002/jmv.70894
Sci Adv. 2026 Mar 27. 12(13): eaee2473

Human NLRP3 inflammasome activation leads to formation of condensate at the microtubule organizing center.

Jue Wang, Man Wu, Le Xiao, Gang Du, Muyuan Chen, Venkat G Magupalli, Peter D Dahlberg, Hao Wu, Grant J Jensen.

The NLRP3 inflammasome is a multiprotein molecular machine that drives inflammatory responses in innate immunity. Although its dysregulation is implicated in numerous human diseases, its structural organization in cells remains poorly understood. Here, we used precise fluorescence-guided cryo-focused ion beam (cryo-FIB) milling and cryo-electron tomography (cryo-ET) to visualize NLRP3 inflammasomes in situ within human macrophages at various stages of activation. After priming and activation, we observed expansion and dispersion of Golgi cisternae, along with the emergence of 50-nanometer NLRP3-associated vesicles, which likely transport NLRP3 to the MTOC. Dense NLRP3-containing condensates then formed in and around the MTOC. In later stages, the condensates solidified, coincident with widespread mitochondrial damage, autophagy, and pyroptotic cell death.

DOI: https://doi.org/10.1126/sciadv.aee2473
Biochem Soc Trans. 2026 Mar 25. pii: BST20250259. [Epub ahead of print]54(3):

Sensing of double-stranded RNA in human cells: molecular mechanisms and cellular consequences.

Julia Cieslicka, Karolina Pianka, Karolina Drazkowska, Pawel J Sikorski.

  Double-stranded RNA (dsRNA) is a universal indicator of viral replication and dysregulated RNA metabolism. Detection of dsRNA triggers some of the most powerful innate immune responses in human cells. Although these molecules differ in origin and structure, viral dsRNAs share the defining geometric and electrostatic features of the A-form helix, enabling their sequence-independent recognition by multiple sensor systems. Cytosolic receptors, like retinoic acid-inducible gene I (RIG-I), melanoma differentiation associated gene 5 (MDA5), and protein kinase R (PKR), as well as the oligoadenylate synthase (OAS)/RNase L pathway, convert dsRNA binding into interferon induction, translational arrest, and widespread RNA decay, while endosomal Toll-like receptor 3 (TLR3) and the inflammasome sensor NLR family pyrin domain containing 1 (NLRP1) expand surveillance to internalised or structurally disruptive RNAs. Counterbalancing these pathways, the RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) marks endogenous dsRNA through A-to-I conversion, preventing inadvertent activation of innate immune response and maintaining self versus non-self discrimination. Although all of these sensors recognise the A-form helix, each extracts distinct structural and chemical information from dsRNA and converts it into a specific response: RIG-I detects short duplexes with 5'-triphosphorylated ends; MDA5 assembles cooperatively along long uninterrupted helices; PKR integrates duplex length with translational control; OAS proteins act as strict reporters of helix regularity; and TLR3 as well as NLRP1 respond to dsRNA in compartment- and context-dependent ways. Epitranscriptomic marks and chemical modifications-including 2'-O-methylation, N6-methyladenosine, pseudouridine, and ADAR1-mediated inosine-further refine sensing by modulating helical stability and end structure, establishing a biochemical 'self-code' that shapes RNA immunogenicity. Together, these pathways form an integrated network that distinguishes between viral and endogenous dsRNA and coordinates antiviral defence with immune tolerance.

Keywords:  RNA modifications; antiviral response; double-stranded RNA; innate immune sensing; self vs non-self discrimination

DOI:  https://doi.org/10.1042/BST20250259
Autophagy. 2026 Apr;22(4): 645-647

Cytosol-dwelling bacteria engage in a ubiquitination race to avoid antibacterial autophagy.

Hana Popelka, Daniel J Klionsky.

  One of the defense mechanisms of host cells against bacterial pathogens is antibacterial macroautophagy/autophagy that relies on ubiquitination of a pathogen for recognition by specific receptors that deliver the pathogen to phagophores. RNF213 is an E3 ligase that mediates ubiquitination of lipopolysaccharides (LPS) on bacteria dwelling in the host cytosol. However, one type of cytosol-invading bacteria, Shigella flexneri, evolved a mechanism through which it can avoid LPS ubiquitination. S. flexneri employs IpaH1.4, an effector protein with E3 ligase activity that ubiquitinates RNF213 for proteasomal degradation. Here, we discuss a study that discovered this S. flexneri strategy, and revealed by cryo-EM that the IpaH1.4 leucine-rich repeat recognizes and binds the RNF213 RING domain. The mass spectrometry data showed that IpaH1.4 targets several other RING-containing E3 ligases implicated in inflammation and immunity, which opens a new field for xenophagy.Abbreviations: cryo-EM, cryo-electron microscopy; LPS, lipopolysaccharide; LRR, leucine-rich repeat; LUBAC, linear ubiquitin chain assembly complex; NEL, novel E3 ligase; OPTN, optineurin.

Keywords:  Cryo-EM; IpaH; RNF213 RING finger; Shigella flexneri; lipopolysaccharides

DOI:  https://doi.org/10.1080/15548627.2026.2624823
J Exp Med. 2026 May 04. pii: e20251796. [Epub ahead of print]223(5):

DNA-PK interacts with cyclic dinucleotides and inhibits type I interferon responses.

Isabelle K Vila, Yasmine Messaoud-Nacer, Clara Taffoni, Jane Jardine, Roger J Eloiflin, Adeline Augereau, Soumyabrata Guha, Moritz Schussler, Pierre Le Hars, Joe McKellar, Tamara Carvalho, Jeanne Postal, Morgane Chemarin, Joanna Re, Florence Guivel-Benhassine, Raphaëlle Lopez, Kilian Trillet, Jennifer Barrat, Maximin Serbier, Insaf El Mansouri, Charlotte Luchsinger, George P Chrousos, Françoise Porrot, Felipe Diaz-Griffero, Olivier Schwartz, Fabien P Blanchet, Karim Majzoub, Nicolas Bidère, Dimitrios Vlachakis, Nadine Laguette.

Inflammatory signal termination is critical for the maintenance of homeostasis. Cyclic dinucleotides (CDNs) are second messengers that trigger inflammatory responses through the activation of the stimulator of IFN genes (STING) signaling platform. No broad-acting direct regulator of intracellular CDNs has been identified in mammals to date. We show that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a major DNA damage response actor, directly interacts with the intracellular 2'3'-cGAMP CDN through its kinase domain, tempering STING activation. DNA-PKcs also acts on the 3'3'-cGAMP bacterial CDN and pharmacological STING agonists, impacting their bioactivity and ability to mount optimal antiviral responses. STING agonism has been considered as a therapeutic avenue to alleviate immunosuppression in human pathologies. By uncovering DNA-PKcs as a CDN signaling modulator and CDNs as inhibitors of DNA-PKcs kinase activity, we provide critical insights into CDN regulation, with implications for the development of STING-targeting therapeutics.

DOI: https://doi.org/10.1084/jem.20251796
Microb Pathog. 2026 Mar 20. pii: S0882-4010(26)00181-6. [Epub ahead of print]215 108455

Salmonella Enteritidis SpaO protein regulating inflammasome activation in macrophage.

Dan Gu, Tianlong Sun, Ang Li, Xiaofang Hu, Xinan Jiao, Zhiming Pan.

  Activation of the inflammasome plays a critical role in host defense against Salmonella infection, yet the bacterial factors governing this process remain poorly defined. Thus, we constructed a transposon mutant library of Salmonella enterica subspecies enterica serovar Enteritidis (S. Enteritidis C50336ΔfliC) to identify the genes involved in inflammasome activation in the macrophage J774A.1. Out of 2639 mutants, seven strains exhibited influence the inflammasome activation, and spaO was selected for further investigation. Compared with the ΔfliC infection group, infection with the ΔfliCΔspaO strain significantly reduced lactate dehydrogenase (LDH) release and secretion of IL-1β and IL-18. Cleaved Caspase-1 and GSDMD were also decreased in macrophage infection with ΔfliCΔspaO, indicating that SpaO is required for inflammasome activation. Consistent results were confirmed in bone marrow-derived macrophages (BMDMs), and we further found that SpaO is required for activation of both NLRC4 and NLRP3 inflammasomes. In a mouse oral infection model, ΔfliCΔspaO infected mice exhibited significantly reduced weight loss, mortality, and bacterial loads in spleen and liver compared with the ΔfliC group. Correspondingly, serum levels of IL-1β and IL-18 were markedly decreased, further supporting the role of SpaO in promoting inflammasome activation in vivo. Moreover, we found that SpaO regulates inflammasome activation maybe by influencing the secretion of the T3SS1 effectors SipB and SipC. Collectively, these findings reveal that SpaO is an important T3SS1 component required for efficient inflammasome activation and virulence of S. Enteritidis, advancing our understanding of bacterial modulation of host innate immunity.

Keywords:  Inflammasome activation; Salmonella Enteritidis; SpaO; Virulence

DOI:  https://doi.org/10.1016/j.micpath.2026.108455
Cell Chem Biol. 2026 Mar 26. pii: S2451-9456(26)00069-3. [Epub ahead of print]

Too much of a good thing: Promotion of tumor progression and metastasis by apoptotic cells.

Cassidy E Hagan, Andrew Oberst.

  Nearly all cancer therapies seek to induce the death of tumor cells. In most cases, they do so by triggering the programmed cell death process of apoptosis, often inducing substantial apoptosis in non-tumor tissues as well as within the tumor itself. Apoptotic cells do not simply disappear from the body; they are cleared by professional and non-professional phagocytes, and during this process, apoptotic cells release soluble signaling molecules and induce phenotypic changes in the phagocytes into which they are absorbed. While much attention has been paid to re-engaging and enhancing tumor cell apoptosis during therapy, emerging evidence suggests that signals emanating from apoptotic cells may promote primary tumor growth and metastatic spread. Here, we summarize the immune suppressive and pro-proliferative effects of apoptotic cells, evidence for their impact on primary tumor growth and metastasis, and strategies that may limit the pro-tumor effects of apoptosis.

Keywords:  apoptosis; cancer; cell death; macrophages; metastasis

DOI:  https://doi.org/10.1016/j.chembiol.2026.02.014
PLoS Pathog. 2026 Mar 27. 22(3): e1014089

Liquid-liquid phase separation mediated immune evasion of respiratory syncytial virus against oligoadenylate synthetase-RNase L pathway.

Woo Yeon Hwang, Michael G Rosenfeld, Soohwan Oh, Young-Chan Kwon.

Respiratory syncytial virus (RSV) infection is the major cause of severe respiratory illnesses in infants and older adults. RSV forms phase-separated biomolecular condensates called inclusion bodies (IBs), which serve as hubs for viral replication. However, the contribution of IBs to host immune response evasion remains elusive. We report that RSV IBs protect viral RNA from the 2'-5' oligoadenylate synthetase (OAS)-RNase L pathway, a critical antiviral defense mechanism that cleaves viral and cellular RNAs. RSV infection did not activate the OAS-RNase L pathway, and ectopically activated RNase L did not suppress viral replication. In RSV-infected cells, double-stranded RNA (dsRNA) was efficiently sequestered within liquid-liquid phase separation (LLPS)-mediated IBs, rendering its detection challenging. LLPS perturbation caused dsRNA release from IBs into the cytosol. dsRNA extracted from infected cells, which lacked LLPS shielding, triggered OAS-RNase L pathway activation. Thus, LLPS-driven IBs structurally sequester viral RNA, facilitating RSV to evade RNase-dependent genomic RNA degradation mediated by the OAS-RNase L antiviral pathway.

DOI: https://doi.org/10.1371/journal.ppat.1014089
Trends Biochem Sci. 2026 Mar 20. pii: S0968-0004(26)00034-4. [Epub ahead of print]

AMPK as a regulatory node in cell death.

Dade Rong, Shuai You, Han-Ming Shen.

  Adenosine Monophosphate (AMP)-activated protein kinase (AMPK) is a critical kinase in the control of cellular metabolism, and in recent years, accumulating evidence has demonstrated that AMPK plays a critical role in the regulation of various types of regulated cell death (RCD) pathways, including apoptosis, necroptosis, pyroptosis, and ferroptosis. In this review, we will first discuss the regulatory roles of AMPK in these forms of RCD. Then, we will examine the implications of AMPK in diseases such as cancer, diabetes complications, ischemia-reperfusion injury, and infectious diseases, focusing on the therapeutic potential of AMPK activators and inhibitors through the regulation of different types of RCD.

Keywords:  AMPK; apoptosis; ferroptosis; necroptosis; pyroptosis

DOI:  https://doi.org/10.1016/j.tibs.2026.02.006