bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2025–11–30
twenty-two papers selected by
Kateryna Shkarina, Universität Bonn
  1. Human non-canonical inflammasomes activate CASP3 to limit intracellular Salmonella replication in macrophages.
  2. Atomic mechanisms of full-length ASC-mediated inflammasome assembly.
  3. Disrupting the TRAF1/cIAP2 interaction attenuates inflammasome activation and protects against monosodium urate crystal-induced arthritis.
  4. Virus-like particle capture reveals coordination of actin remodeling during Shigella flexneri entry by host proteins.
  5. Staphylococcus aureus induces Gasdermin A-dependent keratinocyte pyroptosis.
  6. CED-3 caspase promotes dismantling but not onset of non-apoptotic linker cell death in C. elegans.
  7. Get with the program: regulation of T cell death.
  8. Regulated necrosis at the crossroads of liver inflammation and cancer development.
  9. UFMylation of 14-3-3ε coordinates MAVS signaling complex assembly to promote antiviral innate immune induction.
  10. NLRP3-induced systemic inflammation controls the development of JAK2V617F mutant myeloproliferative neoplasms.
  11. Sibiriline, a novel dual inhibitor of necroptosis and ferroptosis, prevents RIPK1 kinase activity and (phospho)lipid peroxidation as a potential therapeutic strategy.
  12. Chronic sensing of host-derived lipids is an all-in-one signal that primes and activates NLRP3.
  13. Interferon signaling promotes early neutrophil recruitment after zebrafish heart injury.
  14. Itaconate transport across the plasma membrane and Salmonella-containing vacuole via MCT1/4 modulates macrophage antibacterial activity.
  15. Dynamic S-acylation of GSDMA regulates pyroptosis.
  16. Cell size modulates ferroptosis susceptibility.
  17. NF-κB driven inflammation mediates loss of upper airway epithelial tolerance to Streptococcus pneumoniae during influenza co-infection.
  18. Inhibition of oligomeric BAX by an anti-apoptotic dimer.
  19. The Shigella flexneri effector IpaH1.4 facilitates RNF213 degradation and protects cytosolic bacteria against interferon-induced ubiquitylation.
  20. Mechanical confinement induces ferroptosis through mitochondrial dysfunction.
  21. A TLR7/9-IFNα-LDHB axis drives vital NET release and compromises antibacterial defense in lupus.
  22. IL-1R1-positive dorsal raphe neurons drive self-imposed social withdrawal in sickness.
  1. bioRxiv. 2025 Nov 08. pii: 2025.10.31.685927. [Epub ahead of print]
    Human non-canonical inflammasomes activate CASP3 to limit intracellular Salmonella replication in macrophages.
    Madhura Kulkarni, Christopher M Bourne, Ashutosh B Mahale, Patrick M Exconde, Cecelia Murphy, Sofia Cervantes, Matilda Kardhashi, Mirai Kambayashi, William Yoo, Tristan J Wrong, Robert C Patio, Bohdana M Discher, Cornelius Y Taabazuing.
      Inflammasomes are multiprotein signaling platforms that activate inflammatory caspases to initiate innate immune signaling. In humans, canonical inflammasomes activate CASP1, which cleaves the pore-forming protein gasdermin D (GSDMD) and the cytokines IL-1β and IL-18. In contrast, the non-canonical inflammasome detects bacterial lipopolysaccharide (LPS) through CASP4/5, which cleave GSDMD to drive pyroptosis. While CASP1 substrates are well characterized, CASP4/5 substrates remain less defined. Here, we show that in response to intracellular LPS and gram-negative bacterial infection, CASP4/5 directly cleave and activate the executioner caspases CASP3/7. CASP3 in turn cleaves and activates gasdermin E (GSDME). Surprisingly, CASP3, but not GSDME, was required for restricting intracellular Salmonella replication, suggesting that CASP4/5-induced apoptosis contributes to host defense. We further show that most GSDMD cleavage during non-canonical inflammasome activation is mediated by CASP1, and that GSDMD is the primary driver of pyroptosis. Finally, we confirm that CASP4/5 activate CASP3/7 and GSDME in human primary macrophages. These findings establish CASP4/5 as dual apoptotic initiator and inflammatory caspases and reveal a central role for the apoptotic signaling cascade in non-canonical inflammasome-mediated immunity.
    DOI:  https://doi.org/10.1101/2025.10.31.685927
  2. Nat Commun. 2025 Nov 26. 16(1): 10564
    Atomic mechanisms of full-length ASC-mediated inflammasome assembly.
    Dongmei Xue, Fengyun Ni, Sheng Liu, Huifang Yan, Zhenwei Luo, Gang Fu, Qinghua Wang, Jianpeng Ma.
      ASC (Apoptosis-associated Speck-like protein containing a CARD) is a key adaptor protein that assembles inflammasomes by linking sensors such as NLRP3 to effectors like Caspase-1 via its PYD and CARD Death Domains. Due to ASC's propensity to self-aggregate, most high-resolution structural studies focused on isolated PYD or CARD domains, leaving the atomic basis of full-length ASC assembly unknown. Here we determine atomic-resolution cryo-EM structures of PYD and CARD filaments from full-length ASC, revealing characteristic multitrack bundles composed of alternating ASCPYD and ASCCARD filaments that expose multiple interfaces for flexible assembly and efficient signaling. We further show that Caspase-1 filaments nucleate specifically from the B-end of ASCCARD filaments, and that the interdomain linker modulates bundle formation. The ASC isoform ASCb, with a four-residue linker, adopts a distinct architecture, correlating with reduced Caspase-1 activation efficiency. In ASC⁻/⁻ THP-1 cells, only wild-type ASC, not interface-disrupting mutants, restored ASC speck formation and Caspase-1 activation, underscoring the requirement for intact multitrack bundles. Cryo-electron tomography captures snapshots of higher-order inflammasome structures. These findings collectively define the structural and functional principles by which ASC organizes inflammasomes to amplify immune signaling.
    DOI:  https://doi.org/10.1038/s41467-025-65578-2
  3. Immunohorizons. 2025 Nov 24. pii: vlaf065. [Epub ahead of print]9(12):
    Disrupting the TRAF1/cIAP2 interaction attenuates inflammasome activation and protects against monosodium urate crystal-induced arthritis.
    Sahib Singh Madahar, Ali Mirzaesmaeili, Jonathan Raspanti, Yitian Tang, Ali A Abdul-Sater.
      Tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) regulates NF-κB signaling and is implicated in chronic autoimmune diseases characterized by persistent inflammation. In addition to its role in restraining linear ubiquitin assembly complex-mediated linear ubiquitination of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) to limit inflammasome activation, TRAF1 also stabilizes cellular inhibitor of apoptosis protein 2 (cIAP2) by protecting it from degradation. Notably, cIAP2 promotes inflammasome activation via K63-linked polyubiquitination of caspase-1. Here, we show that disrupting the TRAF1/cIAP2 interaction (V203A in humans; V196A in mice) reduces inflammasome activation. TRAF1V203A THP-1 cells exhibit diminished caspase-1 ubiquitination, leading to impaired IL-1β secretion. Similarly, TRAF1V196A mice produce significantly lower IL-1β levels after LPS challenge. In a monosodium urate crystal-induced arthritis model, TRAF1V196A mice show reduced joint inflammation, decreased synovial immune cell infiltration, and attenuated disease severity. These findings establish the TRAF1/cIAP2 axis as a key regulator of inflammasome activation and a potential therapeutic target for inflammasome-driven diseases such as gout.
    Keywords:  TRAF1; cIAP2; crystal-induced arthritis; inflammasomes; ubiquitination
    DOI:  https://doi.org/10.1093/immhor/vlaf065
  4. bioRxiv. 2025 Oct 22. pii: 2025.10.21.683715. [Epub ahead of print]
    Virus-like particle capture reveals coordination of actin remodeling during Shigella flexneri entry by host proteins.
    María Luisa Gil-Marqués, Matthew S Fish, Le Anh Thu Pham, Vritti Kharbanda, Keith T Egger, Marcia B Goldberg, Poyin Chen.
      Shigella spp. are intracellular bacterial pathogens that enter the host via plasma membrane insertion of a type 3 secretion system (T3SS) translocon, which triggers signaling cascades that include modulation of cytoskeletal dynamics, resulting in bacterial uptake. To better understand translocon insertion-induced host processes, we adapted a method to capture in virus-like particles (VLP) host proteins that are recruited to the cytosolic face of natively delivered S. flexneri translocons. Proteomic analyses reveal enrichment of 14-3-3ζ, a signaling protein, and CAP2, a regulator of actin turnover. 14-3-3ζ and CAP2 are necessary for host entry by T3SS pathogens. 14-3-3ζ dimers function as molecular scaffolds in the formation of bacterial-associated membrane ruffles. Concurrently, CAP2 localizes to membrane ruffles and cooperates with 14-3-3ζ to enable the formation of membrane ruffles that function efficiently in bacterial uptake. The findings define a coordinated role for 14-3-3ζ and CAP2 in cytoskeletal dynamics during T3SS pathogen infection.
    DOI:  https://doi.org/10.1101/2025.10.21.683715
  5. Nat Commun. 2025 Nov 26. 16(1): 10570
    Staphylococcus aureus induces Gasdermin A-dependent keratinocyte pyroptosis.
    Doris L LaRock, Jacob D Sherman, Claire Qu, William Ngai, Timothy D Read, Martin J McGavin, Christopher N LaRock.
      Staphylococcus aureus is a common colonizer of human skin, which, despite its ubiquitous nature, has a high virulence potential. Tolerating microbes in health but responding effectively to pathogens presents a challenge to the barrier tissues. Here, we examined the interaction of S. aureus with skin keratinocytes to study this early step of pathogenesis and pathogen discrimination. During infection, the S. aureus protease Staphopain A (ScpA) cleaves inert Gasdermin A (GSDMA). This releases an active N-terminal fragment similar to that formed by host protease regulators of other gasdermins family members. The resulting cell death by pyroptosis allows keratinocytes to deprive invasive S. aureus of an intracellular niche. These data support a model of GSDMA as an autonomous sensor of pathogenicity, in contrast to the conventional regulation of other gasdermins, which have dedicated host cell pathways. Gasdermins abundant in other tissues may have similar functions in host defense for the threat assessment of a microbe.
    DOI:  https://doi.org/10.1038/s41467-025-65674-3
  6. bioRxiv. 2025 Oct 15. pii: 2025.10.15.682583. [Epub ahead of print]
    CED-3 caspase promotes dismantling but not onset of non-apoptotic linker cell death in C. elegans.
    Olya Yarychkivska, Lena M Kutscher, Dana Mamriev, Betty Ortiz Bido, Yun Lu, Wolfgang Keil, Sarit Larisch, Shai Shaham.
      Nuclear degradation accompanies cell death. To study this process, we followed nuclear dismantling of the C. elegans linker cell, which undergoes a non-apoptotic morphologically-conserved death program characterized by nuclear envelope crenellations and cell splitting. We show that although linker cell death is cell autonomous, nucleus elimination follows engulfment and is blocked in rab-35 and arf-6 phagosome maturation mutants. Surprisingly, although linker cell death is independent of the apoptotic caspase CED-3, CED-3 is partially required within the linker cell, and upstream of RAB-35 and ARF-6, for cell splitting, engulfment, and nucleus elimination. In parallel studies, we found that the kinase inhibitor staurosporine causes mouse embryonic fibroblasts to undergo caspase-independent non-apoptotic death accompanied by nuclear crenellations and, paradoxically, by Caspase-3 activation. Our findings suggest mechanistic similarities between staurosporine-induced and linker cell death, revealing that, in some contexts, caspases do not initiate cell death but instead promote subcellular tasks required for cell clearance.
    Keywords:  C. elegans; LCD; MEF; arf-6; caspase; ced-3; degradation; engulfment; linker cell; linker cell-type death; mouse embryonic fibroblasts; non-apoptotic cell death; nuclear crenellation; rab-35; staurosporine
    DOI:  https://doi.org/10.1101/2025.10.15.682583
  7. Trends Immunol. 2025 Nov 25. pii: S1471-4906(25)00272-8. [Epub ahead of print]
    Get with the program: regulation of T cell death.
    Timothy Patton, Hosna Sarani, Nazli Somuncuoglu, Kate E Lawlor, Alexandra J Corbett.
      Programmed cell death (PCD) encompasses several tightly regulated molecular signalling pathways, leading to the controlled destruction of cells. Apoptosis is a non-immunogenic form of cell death that regulates homeostasis to cell stressors. In contrast, lytic forms of cell death - necroptosis, pyroptosis, and ferroptosis - promote inflammation, alerting the immune system to danger. As adaptive immune responders, T cells clonally expand in response to antigenic stimulation and rapidly contract following the clearance of infection. While the role of apoptosis in regulating these processes is relatively well understood, evidence for lytic death activity in T cells is emerging. This review provides an update on recent advances in the understanding of PCD pathways in conventional and unconventional T cells in diverse immune contexts.
    Keywords:  T cell homeostasis; apoptosis; immune regulation; inflammation; necroptosis; pyroptosis
    DOI:  https://doi.org/10.1016/j.it.2025.10.015
  8. Nat Rev Gastroenterol Hepatol. 2025 Nov 24.
    Regulated necrosis at the crossroads of liver inflammation and cancer development.
    Mihael Vucur, Vangelis Kondylis, Petr Broz, Tom Luedde.
      Regulated cell death is a hallmark of inflammatory liver disease, and its intensity influences disease progression and severity. However, it is now clear that the form of cell death could also have an important role. In addition to apoptosis, various forms of regulated necrosis are increasingly reported to contribute to inflammatory liver disease due to their lytic nature. In this Review, we discuss the key regulatory molecules that govern regulated necrosis pathways and summarize our current understanding of the involvement of necroptosis, pyroptosis and ferroptosis in liver injury in preclinical murine models of acute and chronic liver disease and liver cancer development. Furthermore, we highlight the existing controversies and knowledge gaps regarding the relevance of these cell death modalities in hepatocytes and non-hepatocytic liver cells as well as the emerging mechanisms controlling these pathways. Finally, we discuss efforts to specifically modulate these regulated cell death pathways in liver disease and hepatocarcinogenesis in the attempt to prevent liver disease progression or to elicit more potent antitumour immune responses. Outstanding issues and methodological advances that will help to translate preclinical findings into therapeutic applications are also presented.
    DOI:  https://doi.org/10.1038/s41575-025-01147-8
  9. bioRxiv. 2025 Oct 21. pii: 2025.10.21.683613. [Epub ahead of print]
    UFMylation of 14-3-3ε coordinates MAVS signaling complex assembly to promote antiviral innate immune induction.
    Isaura Vanessa Gutierrez, Moonhee Park, Lauren Sar, Ryan E Rodriguez, Hannah M Schmidt, Daltry L Snider, Gabriella Torres, K Matthew Scaglione, Stacy M Horner.
      Post-translational modifications regulate RIG-I signaling in diverse ways. We previously showed that UFMylation, the covalent attachment of the ubiquitin-fold modifier UFM1 to proteins, enhances RIG-I signaling by promoting its interaction with its membrane-targeting adaptor 14-3-3ε. Here, we map UFM1 conjugation to lysines K50 and K215 on 14-3-3ε and demonstrate how these UFMylation events control RIG-I signaling. Using in vitro and cellular UFMylation assays, we reveal that K50R/K215R mutations abolish UFMylation and reduce type I and III interferon induction following RIG-I activation. Unexpectedly, these mutations do not disrupt 14-3-3ε-RIG-I interaction. Instead, they paradoxically enhance RIG-I interaction with MAVS while simultaneously reducing 14-3-3ε-MAVS interaction. These findings establish UFMylation of 14-3-3ε as an important control that shapes MAVS complex architecture to ensure optimal RIG-I signaling and highlights the broader regulatory role of UFMylation in antiviral innate immunity.
    Importance: Post-translational modifications provide regulatory control of antiviral innate immune responses. Our study reveals that UFMylation of 14-3-3ε is required for RIG-I-mediated innate immune signaling. We demonstrate that conjugation of UFM1 to specific lysine residues on 14-3-3ε enhances downstream signaling events that facilitate interferon induction. It does this by stabilizing 14-3-3ε association with the MAVS signaling complex and coordinating productive complex architecture. By identifying the precise sites of UFMylation on 14-3-3ε and their functional consequences, we provide insights into the regulatory layers governing antiviral innate immunity. These findings complement emerging evidence that UFMylation serves as a versatile modulator across diverse immune pathways. Furthermore, our work highlights how protein chaperones like 14-3-3ε can be dynamically modified to orchestrate complex signaling cascades, suggesting potential therapeutic approaches for targeting dysregulated innate immunity.
    DOI:  https://doi.org/10.1101/2025.10.21.683613
  10. Nat Commun. 2025 Nov 26. 16(1): 10591
    NLRP3-induced systemic inflammation controls the development of JAK2V617F mutant myeloproliferative neoplasms.
    Ruth-Miriam Koerber, Calvin Krollmann, Kevin Cieslak, Elisabeth Tregel, Maria L Saenz, Tim H Brümmendorf, Steffen Koschmieder, Martin Griesshammer, Ines Gütgemann, Conny K Baldauf, Thomas Fischer, Peter Brossart, Carl Christian Kolbe, Eicke Latz, Dominik Wolf, Lino L Teichmann.
      The development of Philadelphia chromosome-negative classical myeloproliferative neoplasms (MPN) involves an inflammatory process that facilitates outgrowth of the malignant clone and correlates with clinical outcome measures. This raises the question to which extent inflammatory circuits in MPN depend on activation of innate immune sensors. Here, we investigate whether NLRP3, which precipitates inflammasome assembly upon detection of cellular stress, drives murine JAK2V617F mutant MPN. Deletion of Nlrp3 within the hematopoietic compartment completely prevents increased IL-1β and IL-18 release in MPN. NLRP3 in JAK2V617F hematopoietic cells, but not in JAK2 wild type radioresistant cells, promotes excessive platelet production via stimulation of the direct thrombopoiesis differentiation pathway, as well as granulocytosis. It also promotes expansion of the hematopoietic stem and progenitor cell compartment despite inducing pyroptosis at the same time. Importantly, NLRP3 inflammasome activation enhances bone marrow fibrosis and splenomegaly. Pharmacological blockade of NLRP3 in fully established disease leads to regression of thrombocytosis, splenomegaly and bone marrow fibrosis. These findings suggest that NLRP3 is critical for MPN development and its inhibition represents a new therapeutic intervention for MPN patients.
    DOI:  https://doi.org/10.1038/s41467-025-65673-4
  11. Cell Death Discov. 2025 Nov 28. 11(1): 552
    Sibiriline, a novel dual inhibitor of necroptosis and ferroptosis, prevents RIPK1 kinase activity and (phospho)lipid peroxidation as a potential therapeutic strategy.
    Claire Delehouzé, Melodie Mallais, Arnaud Comte, Romain Lucas, Blandine Baratte, Sophie Bélal, Axelle Autret, Nathalie Py, Rémy Steinschneider, Lucie Adoux, Benjamin Saintpierre, Franck Letourneur, Thomas Robert, Céline Cougoule, Caio Bomfim, Rémi Planès, David Péricat, Jeannette Chloë Bulinski, Marie-Thérèse Dimanche-Boitrel, Peter Goekjian, Etienne Meunier, Morgane Rousselot, Derek A Pratt, Stéphane Bach.
      In the past two decades, various non-apoptotic pathways of regulated cell death have been identified; a small subset of these, including necroptosis and ferroptosis, manifests the phenotypic features of necrotic death. These two regulated necroses are being extensively studied because of their putative roles in severe acute and chronic pathologies. Moreover, as these regulated necrotic pathways are coactivated in a number of common pathologies, the development of multi-target directed ligands (that is, the use of a polypharmacological strategy) is a path-breaking avenue of research. In this study, we determined that the 7-azaindole derivative, sibiriline, inhibited both RIPK1-driven necroptosis (induced by Tumor Necrosis Factor-α) and ferroptosis (triggered by various classes of ferroptosis inducers), with EC50s against each in the µM range. We next performed a combined large-scale transcriptomic study in order to determine the molecular mechanisms of action of sibiriline. We identified the stress response protein heme oxygenase-1 (HMOX1) as the main biomarker of ferroptosis inhibition by sibiriline. We hypothesized that this compound reacts as an antioxidant to block ferroptosis; indeed, we found that sibiriline inhibits lipid peroxidation by trapping phospholipid-derived peroxyl radicals as a radical-trapping antioxidant (RTA). Taken together, these results show that sibiriline is a new dual inhibitor of necroptosis and ferroptosis cell death pathways; it works by inhibition of both RIPK1 kinase and (phospho)lipid peroxidation. We also demonstrate the in vitro efficacy of sibiriline to inhibit cell death in cell-based models of Parkinson's disease and cystic fibrosis. These findings shed light on the high therapeutic potency of RIPK1 inhibitors with RTA activity.
    DOI:  https://doi.org/10.1038/s41420-025-02852-8
  12. bioRxiv. 2025 Oct 30. pii: 2025.10.29.685328. [Epub ahead of print]
    Chronic sensing of host-derived lipids is an all-in-one signal that primes and activates NLRP3.
    Océane Dufies, Marco Di Gioia, Roberto Spreafico, Piao J Tan, James R Springstead, Sean A Prell, Junning Case, Ce Gao, Kevin Wei, Hao Wu, Ivan Zanoni.
      Activation of the NLRP3 inflammasome leads to the production of bioactive interleukin (IL)-1β fostering atherosclerosis. The current dogma is that NLRP3 must be first primed by microbial stimuli, known as pathogen-associated molecular patterns (PAMPs), and then activated by either microbial or host-derived inflammatory cues. The mechanism that controls NLRP3 functioning in the context of non-communicable diseases lacking overt microbial infections remains debated. Here, we show that chronic exposure to atherosclerosis-associated oxidized phospholipids (oxPLs) simultaneously primes and activates NLRP3 independently of microbial cues. Mechanistically, chronic exposure to host-derived oxPLs activate the transcription factor NRF2, which is necessary and sufficient to prime and activate NLRP3 in a PAMP-independent manner. NRF2 chronic activation drives oxidized mitochondrial DNA to activate NLRP3. Ex vivo analyses of atherosclerotic plaques in mice and humans identify a population of monocytes-derived macrophages which activates NRF2 and expresses IL-1β. Overall, our data point to oxPL-dependent NRF2 activation as an all-in-one signal necessary and sufficient to prime and activate NLRP3, sustaining atherogenesis.
    DOI:  https://doi.org/10.1101/2025.10.29.685328
  13. bioRxiv. 2025 Nov 16. pii: 2025.11.16.688717. [Epub ahead of print]
    Interferon signaling promotes early neutrophil recruitment after zebrafish heart injury.
    Alexis V Schmid, James A Gagnon.
      Heart injury triggers a robust cellular response in zebrafish, characterized by neovascularization, immune cell activation, and the infiltration of proliferative cardiomyocytes that collectively lead to scarless regeneration. Upon injury, damage-associated molecular patterns are released by dying cells and injured extracellular matrix. These molecules bind to pattern recognition receptors on various cell types, promoting inflammation and immune cell recruitment by upregulating chemokines and pro-inflammatory cytokines. We previously identified the activation of injury-induced interferon signaling as a distinguishing feature between the regenerative zebrafish and non-regenerative medaka. Here, we establish interferon-Φ1 (IFN□1) as the primary driver of interferon signaling after zebrafish heart injury. IFN□1 expression is induced hours after injury and directs interferon-stimulated gene expression, which peaks at 72 hours post-injury. This response is lost in ifnphi1 mutants, which disrupt IFN□1 expression. ifnphi1 mutants have reduced neutrophil recruitment to the injured myocardium, while macrophages and neovascularization are unaffected. By studying later stages of regeneration, we find that ifnphi1 mutant hearts have a modest defect in scar resolution. Collectively, these findings uncover a critical early signaling cascade during the inflammatory response to heart injury and provide new insights into the mechanisms that choreograph zebrafish heart regeneration.
    DOI:  https://doi.org/10.1101/2025.11.16.688717
  14. Nat Commun. 2025 Nov 26. 16(1): 10551
    Itaconate transport across the plasma membrane and Salmonella-containing vacuole via MCT1/4 modulates macrophage antibacterial activity.
    Qingcai Meng, Chengxi Li, Yuping Cai, Ying Chen, Xiaoqing Chen, Xin Wang, Biling Zhang, Yue Zhang, Feng Liu, Meixin Chen.
      Itaconate accumulates in macrophages upon bacterial infection, and manifests antibacterial activity. Convincing evidence substantiates that itaconate is transported across the plasma membrane and vacuolar membrane, but the molecular bases underlying bidirectional transport of itaconate across membranes and its effects on intracellular bacterial replication are less known. Here, we identify MCT1 and MCT4 as bidirectional transporters of itaconate. In addition to modulating itaconate concentration as transporters at the plasma membrane, MCT1 and MCT4 function as itaconate transporters at Salmonella-containing vacuole (SCV). Upon Salmonella infection, MCT1 and MCT4 transport itaconate into SCV facilitated by RAB32. Itaconate is also secreted out of cells through MCT1 and MCT4 as the infection persists. The suppression of MCT1 and MCT4-dependent itaconate secretion increases the overall concentration of itaconate and the proportion of itaconate-targeted Salmonella intracellularly, consequently inhibiting Salmonella replication. Our study thus offers valuable insights into itaconate transport during bacterial infection and provides proof of principle for the development of itaconate-dependent therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-025-65582-6
  15. bioRxiv. 2025 Oct 16. pii: 2025.10.16.682910. [Epub ahead of print]
    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 remains poorly understood. Here, we demonstrate that GSDMA is S-acylated at the conserved cysteine residues in its N-terminal domain. We show that 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. Additionally, we present evidence that recombinant proteins of GSDMA and GSDMD can undergo S-acylation in vitro via direct interaction with palmitoyl-CoA, suggesting they potentially possess auto-acylation capacity. 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/10.1101/2025.10.16.682910
  16. bioRxiv. 2025 Oct 26. pii: 2025.10.25.684524. [Epub ahead of print]
    Cell size modulates ferroptosis susceptibility.
    Evgeny Zatulovskiy, Magdalena B Murray, Shuyuan Zhang, Scott J Dixon, Jan M Skotheim.
      Size is a fundamental property of cells that influences many aspects of their physiology. This is because cell size sets the scale for all subcellular components and drives changes in the composition of the proteome. Given that large and small cells differ in their biochemical composition, we hypothesize that they should also differ in how they respond to signals and make decisions. Here, we investigated how cell size affects the susceptibility to cell death. We found that large cells are more resistant to ferroptosis induced by system x c - inhibition. Ferroptosis is a type of cell death characterized by the iron-dependent accumulation of toxic lipid peroxides. This process is opposed by cysteine-dependent lipid peroxide detoxification mechanisms. We found that larger cells exhibit higher concentrations of the cysteine-containing metabolite glutathione and lower concentrations of membrane lipid peroxides, compared to smaller cells. Mechanistically, this can be explained by the fact that larger cells had lower concentrations of an enzyme that enriches cellular membranes with peroxidation-prone polyunsaturated fatty acids, ACSL4, and increased concentrations of the iron-chelating protein ferritin and the glutathione-producing enzymes glutamate-cysteine ligase and glutathione synthetase. Taken together, our results highlight the significant impact of cell size on cellular function and survival, revealing a size-dependent vulnerability to ferroptosis that could influence therapeutic strategies based on this cell death pathway.
    DOI:  https://doi.org/10.1101/2025.10.25.684524
  17. bioRxiv. 2025 Oct 26. pii: 2025.10.25.684585. [Epub ahead of print]
    NF-κB driven inflammation mediates loss of upper airway epithelial tolerance to Streptococcus pneumoniae during influenza co-infection.
    Zahrasadat Navaeiseddighi, Zhihan Wang, Kai Guo, Syed Hasan, Taylor Schmit, Jamanah Ahsan, Ramkumar Mathur, Junguk Hur, Nadeem Khan.
      Streptococcus pneumoniae asymptomatically colonizes the human nasopharynx, where epithelial tolerance maintains mucosal homeostasis. However, influenza A virus (IAV) co-infection transforms this tolerogenic state into an inflammatory environment that promotes bacterial outgrowth and invasion. Here, we identify a TGF-β1 dependent epithelial program that sustains mucosal tolerance during Spn colonization and demonstrate that IAV co-infection disrupts this pathway through IL-17RA-NF-κB driven inflammation in the nasopharynx. In a murine colonization model, TGF-β1 blockade enhanced pro-inflammatory cytokine production and neutrophil recruitment, resulting in inflammation-driven Spn clearance. IAV co-infection suppressed epithelial TGF-β1 signaling, increased TRAF6/NF-κB activation, and impaired tight junction integrity, leading to Spn dissemination. Mechanistically, IL-17RA signaling contributed to the hyperactivation of the TRAF6/NF-κB axis. Pharmacologic inhibition of TRAF6 or NF-κB restored epithelial barrier function and reduced Spn translocation in a human air-liquid interface nasopharyngeal epithelial model. These findings reveal a conserved epithelial signaling axis through which influenza disrupts mucosal tolerance and promotes Spn invasion, highlighting the canonical TRAF6-NF-κB pathway as a potential therapeutic target to preserve epithelial integrity and mitigate Spn infection during viral-bacterial co-infection of the upper respiratory tract.
    DOI:  https://doi.org/10.1101/2025.10.25.684585
  18. Cell. 2025 Nov 21. pii: S0092-8674(25)01242-5. [Epub ahead of print]
    Inhibition of oligomeric BAX by an anti-apoptotic dimer.
    Catherine E Newman, Micah A Gygi, Haleh Alimohamadi, Thomas M DeAngelo, Christina M Camara, Julian Mintseris, Ezra Yu, Edward P Harvey, Zachary J Hauseman, Lixin Fan, Yun-Xing Wang, Elizabeth W-C Luo, Marina Godes, Jacob Gehtman, Ann M Cathcart, Steven P Gygi, John R Engen, Gregory H Bird, Gerard C L Wong, Thomas E Wales, Loren D Walensky.
      BAX is a pro-apoptotic BCL-2 protein that resides in the cytosol as a monomer until triggered by cellular stress to form an oligomer that permeabilizes mitochondria and induces apoptosis. The paradigm for apoptotic blockade involves heterodimeric interactions between pro- and anti-apoptotic monomers. Here, we find that full-length BCL-w forms a distinctive, symmetric dimer (BCL-wD) that dissociates oligomeric BAX (BAXO), inhibits mitochondrial translocation, promotes retrotranslocation, blocks membrane-porating activity, and influences apoptosis induction of cells. Structure-function analyses revealed discrete conformational changes upon BCL-w dimerization and reciprocal structural impacts upon BCL-wD and BAXO interaction. Small-angle X-ray scattering (SAXS) analysis demonstrated that BAXO disrupts membranes by inducing negative Gaussian curvature, which is reversed by positive Gaussian curvature exerted by BCL-wD. Systematic truncation and mutagenesis dissected the core features of BCL-wD activity-dimerization, BAXO engagement, and membrane interaction. Our studies reveal a downstream layer of apoptotic control mediated by protein and membrane interactions of higher-order BCL-2 family multimers.
    Keywords:  BAX; BCL-2 family proteins; BCL-w; anti-apoptotic; apoptosis; cell death; chemical crosslinking mass spectrometry; dimer; hydrogen deuterium exchange mass spectrometry; membrane curvature; mitochondria; mitochondrial retrotranslocation; mitochondrial translocation; oligomer; pro-apoptotic; small-angle X-ray scattering
    DOI:  https://doi.org/10.1016/j.cell.2025.10.037
  19. Elife. 2025 Nov 28. pii: RP102714. [Epub ahead of print]13
    The Shigella flexneri effector IpaH1.4 facilitates RNF213 degradation and protects cytosolic bacteria against interferon-induced ubiquitylation.
    Luz Saavedra-Sanchez, Mary S Dickinson, Shruti S Apte, Yifeng Zhang, Maarten De Jong, Samantha Skavicus, Nicholas S Heaton, Neal M Alto, Jorn Coers.
      A central signal that marshals host defense against many infections is the lymphocyte-derived cytokine interferon-gamma (IFNγ). The IFNγ receptor is expressed on most human cells, and its activation leads to the expression of antimicrobial proteins that execute diverse cell-autonomous immune programs. One such immune program consists of the sequential detection, ubiquitylation, and destruction of intracellular pathogens. Recently, the IFNγ-inducible ubiquitin E3 ligase RNF213 was identified as a pivotal mediator of such a defense axis. RNF213 provides host protection against viral, bacterial, and protozoan pathogens. To establish infections, potentially susceptible intracellular pathogens must have evolved mechanisms that subdue RNF213-controlled cell-autonomous immunity. In support of this hypothesis, we demonstrate here that a causative agent of bacillary dysentery, Shigella flexneri, uses the type III secretion system (T3SS) effector IpaH1.4 to induce the degradation of RNF213. S. flexneri mutants lacking IpaH1.4 expression are bound and ubiquitylated by RNF213 in the cytosol of IFNγ-primed host cells. Linear (M1-) and lysine-linked ubiquitylation of S. flexneri requires RNF213 but is independent of the linear ubiquitin chain assembly complex (LUBAC). We find that ubiquitylation of S. flexneri is insufficient to kill intracellular bacteria, suggesting that S. flexneri employs additional virulence factors to escape from host defenses that operate downstream from RNF213-driven ubiquitylation. In brief, this study identified the bacterial IpaH1.4 protein as an inhibitor of mammalian RNF213 and highlights evasion of RNF213-driven immunity as a characteristic of the human-tropic pathogen Shigella.
    Keywords:  E3 ligase; RNF213; Shigella; autophagy; immunology; infectious disease; inflammation; microbiology; ubiquitin; xenophagy
    DOI:  https://doi.org/10.7554/eLife.102714
  20. Nat Commun. 2025 Nov 28.
    Mechanical confinement induces ferroptosis through mitochondrial dysfunction.
    Fang Zhou, Robert J Ju, Chenlu Kang, Jiayi Li, Ao Yang, Alexandre Libert, Yujie Sun, Ling Liang, Youwei Ai, Xiaoqing Hu, Samantha J Stehbens, Congying Wu.
      Cells in highly crowded environments are exposed to fluctuating mechanical forces. While cells can activate the cortical migration machinery to escape from undesirable compressive stress, the consequence to less motile cells and of prolonged extensive confinement is yet to be uncovered. Here, we demonstrate that nuclear deformation generated by axial confinement triggers a specific form of regulated cell death - ferroptosis. We show that axial confinement is sensed by the nucleus and results in Drp1-dependent mitochondrial fragmentation and mitochondrial ROS accumulation. Meanwhile, we detect cPLA2 translocation to mitochondria. These mitochondrial ROS accumulation and arachidonic acid production concertedly lead to lipid peroxidation and evoke ferroptosis. Interestingly, we find in osteoarthritis, a disease intimately associated with mechanical overloading and inflammation, characteristics of confinement-induced ferroptosis including mitochondrial localization of cPLA2 and high ROS. Together, our findings unveil a pivotal role of cell nucleus and mitochondria in linking mechanical confinement with cell death, highlighting the orchestration of Drp1 and cPLA2 in confinement-induced ferroptosis.
    DOI:  https://doi.org/10.1038/s41467-025-66353-z
  21. bioRxiv. 2025 Oct 07. pii: 2025.10.07.680928. [Epub ahead of print]
    A TLR7/9-IFNα-LDHB axis drives vital NET release and compromises antibacterial defense in lupus.
    Eden G TenBarge, Ashley D Wise, Morgan L Hetzel, Helene A Hoover, Helia Esfandiari, Bailey E Holder, Eva Belevska, Ellie C Mennen, Sarah R McDaniel, Nicole M Vaccaro, Courtney C Lucca, Jonathan M Williams, Jennifer Ferris, Timothy E Sparer, Leslie J Crofford, Jeffry D Bieber, Andrew J Monteith.
      Patients with systemic lupus erythematosus (SLE) are susceptible to bacterial infections, but the underlying dysfunction remains unclear. We found that Staphylococcus aureus triggers mitochondria-dependent suicidal NETosis via lactate sensing in healthy neutrophils, but this response is defective in SLE. Herein, we show that chronic Toll-like receptor (TLR) 7/9 signaling represses mitochondrial lactate dehydrogenase B (LDHB), thereby impairing lactate sensing and downstream suicidal NETosis. Instead, SLE neutrophils default to vital NET release; a less bactericidal, type I interferon (IFN)-driven process amplified by staphylococcal pore-forming toxins and sustained by elevated systemic IFNα levels observed in SLE. Combined treatment with hydroxychloroquine (HCQ) and interferon-alpha/beta receptor (IFNAR) blockade restores LDHB expression, NET homeostasis, and bacterial clearance in lupus-prone mice. Neutrophils from SLE patients exhibit similar defects, which are reversed by HCQ and the IFNAR-blocking antibody anifrolumab. These findings identify a clinically actionable immunometabolic checkpoint linking chronic autoimmune signaling to defective antibacterial defense in SLE.
    DOI:  https://doi.org/10.1101/2025.10.07.680928
  22. Cell. 2025 Nov 25. pii: S0092-8674(25)01245-0. [Epub ahead of print]
    IL-1R1-positive dorsal raphe neurons drive self-imposed social withdrawal in sickness.
    Liu Yang, Matias L Andina, Mario Witkowski, Hunter King, Ian Wickersham, Jun R Huh, Gloria B Choi.
      Sick animals exhibit behavioral changes that extend beyond physiological symptoms, such as appetite loss and hypoactivity, and include a decline in social interactions. While social isolation during sickness has been recognized to have the evolutionary benefit of staving off disease spread, the molecular and neural mechanisms underlying this response remain unclear. Cytokines-immune-derived signaling molecules-have emerged as neuromodulators impacting brain function during inflammation. Through behavioral screening, we identify a unique role for the cytokine interleukin-1β (IL-1β) in promoting social withdrawal during sickness. IL-1β directly modulates the activity of IL-1R1-expressing neurons in the dorsal raphe nucleus (DRN) (IL-1R1DRN). Activation of these neurons is sufficient to elicit social withdrawal, while their inhibition or genetic deletion of IL-1R1 rescues self-imposed social isolation during systemic inflammation. Our findings reveal a neural mechanism that actively promotes social disengagement in sick animals, highlighting the role of IL-1R1DRN neurons in driving these behavioral adaptations.
    Keywords:  LPS; cytokine; dorsal raphe nucleus; infection; interleukin-1; neuroimmunology; pathogen; social behavior
    DOI:  https://doi.org/10.1016/j.cell.2025.10.040
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