bims-cediti 2025-10-26 papers

Issue of 2025–10–26
seven papers selected by
Kateryna Shkarina, Universität Bonn

J Biol Chem. 2025 Oct 22. pii: S0021-9258(25)02708-5. [Epub ahead of print] 110856

ZBP1 Orchestrates Dynamic Transitions Between Cell Death Pathways in Response to Arsenic and Hyperosmotic Stress.

Yinghao Fu, Yifan Yang, Qingqing Li, Xin Xia, Menghan Peng, Shanshan Meng, Rong Shen, Yongyi Zhu, Huipeng Jiao, Chun Kim, Juan Lin.

Z-DNA binding protein 1 (ZBP1), a sensor of Z-form nucleic acids, plays a crucial role in cell death and inflammation. While its functions in infection and development are well-established, its involvement in environmental stress responses remains largely unexplored. In this study, we uncovered novel mechanisms by which ZBP1 mediates cell death under arsenic and hyperosmotic stress. We demonstrate that ZBP1 initiates necroptosis during the early stages of these stresses. As the stress persists, the cell death mode evolves, shifting towards apoptosis and pyroptosis in later stages. This transition is particularly pronounced when the necroptotic pathway is compromised. Interestingly, despite previous implications of stress granules (SG) in arsenic-dependent cell death, we found that neither SG formation inhibitors nor the ablation of SG components significantly impacts cell death under arsenic or hyperosmotic stress. This suggests that environmental stress-induced necroptosis operates largely independent of stress granule formation. Employing genome-wide CRISPR/Cas9 library screening, we identified that ZBP1-dependent cell death in response to arsenic is primarily driven by reactive oxygen species (ROS) and the KEAP1-NRF2 signaling pathway. Notably, ZBP1 knockout mice demonstrated resistance to arsenic-induced cell death and tissue injury, further substantiating our findings. Our research provides important new insights into ZBP1's role in environmental stress-induced cell death, expanding our understanding beyond its established functions in infection and development. These findings offer potential implications for comprehending stress-related tissue injury mechanisms.

Keywords: Apoptosis; Necroptosis; Pyroptosis; Stress granules; ZBP1

DOI: https://doi.org/10.1016/j.jbc.2025.110856

Blood Adv. 2025 Oct 20. pii: bloodadvances.2024015623. [Epub ahead of print]

Heme and hemozoin induce platelet cell death through UPR-induced apoptosis and ferroptosis in vivax malaria.

Malaria is a highly prevalent infectious disease caused by Plasmodium parasites. Plasmodium intraerythrocytic replication leads to hemolysis-driven intermittent febrile crisis in patients. Additionally, the lysis of unparasitized red blood cells (RBC) contributes to anemia and endotoxemia. Because thrombocytopenia is an important feature of vivax and severe falciparum malaria, we hypothesized that increased hemolysis in malaria contributes to severe thrombocytopenia by releasing endogenous and parasite toxins (i.e., heme and hemozoin) capable of inducing programmed cell death in platelets. Using complementary biochemical, ultrastructural, pharmacological and molecular approaches, we examined response to stress and cell death pathways that were elevated in the transcriptome of platelets during vivax malaria and evaluated markers of hemolysis that correlated with thrombocytopenia. We found that heme in plasma from thrombocytopenic vivax malaria, but not nonthrombocytopenic vivax or falciparum malaria, induced platelet cell death ex vivo. Platelet stimulation with heme and hemozoin induced apoptotic and necrotic cell death features, with stronger necrosis triggered by hemozoin. Heme and hemozoin activated apoptotic caspases, but only heme induced calpain-dependent Bcl-xL degradation, which was not required for platelet apoptosis. We unmasked a caspase-independent intrinsic apoptosis program mechanism depending on the endoplasmic reticulum (ER)-stress sensor and unfolded protein response (UPR) trigger IRE-Iα. We observed inflammasome activation, but not pyroptosis. Instead, we distinguished a necrotic cell death feature consistent with ferroptosis dependent on lipid peroxidation and regulated by DGAT1/2 enzymes, which was the main pathway for hemozoin-induced thrombocytopenia in vitro. Taken together, our results identify novel pathways of regulated cell death in platelets that were associated with thrombocytopenia in malaria and may have potential implications for other hemolytic disorders.

DOI: https://doi.org/10.1182/bloodadvances.2024015623

Cell Host Microbe. 2025 Oct 22. pii: S1931-3128(25)00413-5. [Epub ahead of print]

Bacterial effector OspB hijacks apoptosis through peptide-bond recombination of BH3 domain proteins.

Yue Shao, Dandan Yang, Xinguang Gao, Minghui Wang, Liyuan Meng, Tianye Niu, Li Xia, Jingjin Ding, Feng Shao, Yue Xu.

Apoptosis is a defense response involving key players, including BH3-only proteins that engage BCL-2 family proteins BAX and BAK, initiating mitochondrial outer membrane permeabilization and caspase activation. However, Shigella flexneri subverts these death pathways to promote infection. Here, we identify the Shigella type III secretion system effector OspB as an enzyme that suppresses apoptosis by targeting BAX and BAK. OspB recognizes BAX/BAK in complex with BH3-only activators, notably tBID, and catalyzes a peptide-bond recombination between their BH3 domains. This reaction generates chimeric proteins comprising the N-terminal BH3-only segment fused to the C-terminal region of BAX or BAK, irreversibly inhibiting protein function and thus mitochondrial outer membrane permeabilization and apoptosis. OspB-mediated apoptosis inhibition enhances S. flexneri virulence in vivo. Homologous effectors with similar catalytic activity are conserved across various bacterial species. These findings reveal a bacterial strategy for apoptosis inhibition via remodeling of BCL-2 family proteins, offering avenues for therapeutic intervention.

Keywords: BCL-2 family proteins; BH3 domain; OspB; Shigella flexneri; T3SS; apoptosis; host-pathogen interaction; peptide-bond recombination

DOI: https://doi.org/10.1016/j.chom.2025.09.018

Cell Death Dis. 2025 Oct 21. 16(1): 742

Cytochrome b5 reductase orchestrates IL-1β production in macrophages through FAD.

Jian Fu, Zhihua Liu, Hangchao Zhang, Xinmei Zhang, Shijie Liu, Xuehua Mei, Xiu Zeng, Wenkai Ren.

The cytochrome-b5 reductases (CYB5Rs) regulate cellular redox balance and contribute to the pathogenesis of inflammatory diseases. However, the roles of CYB5R5 in macrophages remain poorly understood and require further elucidation. In this study, we revealed that CYB5R5 orchestrates macrophage inflammation by inhibiting interleukin (IL)-1β production from M1 macrophages. Mechanistically, CYB5R5 enhances flavin adenine dinucleotide (FAD)-lysine demethylase1 (LSD1) signaling to regulate the histone demethylation of complement component 1, q subcomponent (C1q)-coding genes, thereby lowering NLRP3 inflammasome assembly. We also found that myeloid depletion of Cyb5r5 in mice exacerbates inflammatory responses in LPS-induced sepsis. This study reveals that CYB5R5 attenuates M1 macrophage polarization via metabolic and epigenetic reprogramming mechanism, thus providing potential therapeutic targets for macrophage-mediated inflammatory disorders.

DOI: https://doi.org/10.1038/s41419-025-08073-2

Nat Commun. 2025 Oct 24. 16(1): 9429

Large transient assemblies of Apaf1 constitute the apoptosome in cells.

Alicia C Borgeaud, Iva Ganeva, Calvin Klein, Amandine Stooss, Daniela Ross-Kaschitza, Liyang Wu, Joel S Riley, Stephen W G Tait, Thomas Lemmin, Thomas Kaufmann, Wanda Kukulski.

Upon cell death signals, the apoptotic protease-activating factor Apaf1 and cytochrome c interact to form the apoptosome complex. The apoptosome is crucial for mitochondrial apoptosis, as it activates caspases that dismantle the cell. However, the in vivo assembly mechanism and appearance of the apoptosome remain unclear. We show that upon onset of apoptosis, Apaf1 molecules accumulate into multiple foci per cell. Disassembly of the foci correlates with cell survival. Structurally, Apaf1 foci resemble organelle-sized, cloud-like assemblies. They form through specific interactions with cytochrome c, contain caspase-9, and depend on procaspase-9 expression for their formation. We propose that Apaf1 foci correspond to the apoptosome in cells. Transientness and ultrastructure of Apaf1 foci suggest that the dynamic spatiotemporal organisation of apoptosome components regulates progression of apoptosis.

DOI: https://doi.org/10.1038/s41467-025-64478-9

Nature. 2025 Oct 22.

Enteropathogenic bacteria evade ROCK-driven epithelial cell extrusion.

Giovanni Luchetti, Marin V Miner, Rachael M Peterson, William P Scott, Praveen Krishnamoorthy, Eric M Kofoed, Angel G Jimenez, Hua Zhang, Man Wah Tan, Rohit Reja, Tommy K Cheung, Elizabeth Skippington, Yuxin Liang, Christopher M Rose, Nobuhiko Kayagaki, Kim Newton, Isabella Rauch, Vishva M Dixit.

Diverse pathogen-encoded virulence factors disable apoptosis, pyroptosis or necroptosis, the host cell death programs that remove infected cells1. In the intestine, the extrusion of infected cells into the lumen for elimination provides an additional layer of host defence, but no virulence mechanisms that target the cytoskeletal changes required are known2. Here we show that the Escherichia coli ubiquitin ligase NleL is an inhibitor of intestinal epithelial cell (IEC) extrusion, targeting caspase-4, ROCK1 and ROCK2 for proteasomal degradation. Genetic deletion of Rock1 and Rock2 from cultured IECs diminished inflammasome-induced IEC extrusion. Moreover, mice with Rock1- and Rock2-deficient IECs were less effective than wild-type mice at constraining the numbers of Citrobacter rodentium in the colon. Notably, NleL-deficient C. rodentium triggered more IEC extrusion than did wild-type C. rodentium, resulting in diminished colonization of the colon in infected mice. Our work highlights a host-pathogen arms race focused on dynamic regulation of the host epithelial barrier.

DOI: https://doi.org/10.1038/s41586-025-09645-0

J Cell Biol. 2026 Jan 05. pii: e202501165. [Epub ahead of print]225(1):

Fibroblasts promote osmotic surveillance by wound-induced unique calcium patterns.

László Fazekas, Diána Kaszás, Boldizsár Vámosi, Szimonetta Xénia Tamás, Tamás Szöllősi, Vivien Mihályi, Fabian Gregor Dehne, Klaudia Vágó-Kiss, Nada Mohamed Al-Sheraji, Barnabás Paulovits, Benoit Thomas Roux, Balázs Enyedi.

Fibroblasts are pivotal in tissue homeostasis, contributing to tissue repair and environmental sensing. Studying their role in zebrafish has been hampered by the lack of robust transgene expression tools. Here, we developed a fin fibroblast-specific synthetic promoter by combining the zebrafish itga11a regulatory region with the murine cFos minimal promoter. Establishing this itga11a-cFos promoter in the QF2-QUAS system enabled evaluation of damage-induced signaling pathways in fibroblasts using genetically encoded biosensors. Our findings reveal that fibroblasts generate spatially distinct, sustained calcium signals in response to epithelial injury, in contrast to transient oscillatory signals in keratinocytes. These calcium signals are modulated by external osmotic cues, highlighting a role for fibroblasts in osmotic surveillance. We also show that tissue damage activates the cPla2-mediated shape-sensing and nuclear swelling-dependent pathways in fibroblasts. Our results demonstrate the versatility of the itga11a-cFos promoter in driving fibroblast-specific expression of biosensors and ablation tools. Using this toolkit, we provide new insights into damage-induced signaling pathways in fibroblasts.

DOI: https://doi.org/10.1083/jcb.202501165