bims-cediti 2025-10-05 papers

Issue of 2025–10–05
four papers selected by
Kateryna Shkarina, Universität Bonn

J Microbiol. 2025 Sep;63(9): e2508004

Bak and Bax are crucial for Gbp2-mediated pyroptosis during Vibrio and Salmonella infections.

Pyroptosis a lytic form of programmed cell death, is a crucial host defense mechanism against bacterial pathogens. While caspase-mediated pathways are central to pyroptosis, the involvement of apoptotic regulators such as Bak, Bax, and MCL-1 in bacterial infection-induced pyroptosis remains unclear. Here, we investigated how these BCL-2 family proteins modulate pyroptosis induced by Vibrio vulnificus and Salmonella enterica serovar Typhimurium in murine cells. In mouse embryonic fibroblasts (MEFs), both pathogens strongly induced Gbp2 expression and activated caspase‑11, whereas activation of caspase‑1 occurred only in macrophages, indicating engagement of both non-canonical and canonical pyroptosis pathways. Importantly, Bak-/- and Bax-/- MEFs exhibited significantly reduced Gbp2 upregulation and caspase-11 activation-an effect most pronounced in Bak-deficient cells leading to attenuated pyroptotic cell death. These data suggest that pro-apoptotic proteins, Bak and Bax, act as positive regulators that amplify the Gbp2-caspase-11 axis. Conversely, overexpression of the anti-apoptotic protein MCL‑1 had no significant impact on Gbp2 expression, caspase activation, membrane integrity, or LDH release, indicating that pyroptosis proceeds independently of MCL‑1 regulation. Collectively, our findings uncover a novel role for Bak and Bax in promoting Gbp2-driven pyroptosis during Gram-negative bacterial infections, while MCL‑1 does not impede this process. This work expands our understanding of the crosstalk between apoptotic and pyroptotic pathways in innate immune responses.

Keywords: Bak; Bax; Salmonella; Vibrio; guanylate binding protein; pyroptosis

DOI: https://doi.org/10.71150/jm.2508004

Curr Opin Cell Biol. 2025 Sep 26. pii: S0955-0674(25)00121-8. [Epub ahead of print]97 102583

Dynamic regulation of cell death signaling.

Asma Majoul, Ana J Garcia-Saez.

There are many ways for a cell to die, but each cell only dies once, causing an inherent variability that results from common triggers activating interconnected signaling networks that diverge at key decision points during cell death initiation, progression, and execution. Despite the death of each cell being a unique biomolecular event, shared features allow us to categorize the process depending on the pathways activated and their outcomes. Here we outline core concepts about the dynamic interplay between cell death pathways, focusing on apoptosis, necroptosis, pyroptosis, and ferroptosis. We highlight unresolved decision points, including the dynamics of pore formation and the points of no return. We also discuss conceptual commonalities across systems and outline key recent developments that refine our understanding of the dynamic regulation of cell death.

DOI: https://doi.org/10.1016/j.ceb.2025.102583

bioRxiv. 2025 Sep 27. pii: 2025.09.25.678451. [Epub ahead of print]

GBP1 recruitment to actin-rich pedestals induced by extracellular Gram-negative bacteria promotes pyroptosis.

Daniel J Bennison, Ishaan Chaudhary, Dharitri Chaudhuri, Justin Chun Ngai Wong, Priyanka Biswas, Qiyun Zhong, Wouter W Kallemeijn, Marianne Guenot, Arthur M Talman, Eva-Maria Frickel, Edward W Tate, Sandhya S Visweswariah, Gad Frankel, Avinash R Shenoy.

The IFNγ-induced GTPase guanylate binding protein 1 (GBP1) binds to lipopolysaccharide (LPS) on cytosolic Gram-negative bacteria and promotes pyroptosis via the recruitment and activation of caspase-4 on the bacterial outer membrane. Enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC, respectively) are extracellular pathogens that also induce LPS- and caspase-4-dependent pyroptosis. However, whether GBP1 is involved in this process remains unknown. EPEC and EHEC adhere intimately to intestinal epithelial cells via avid interactions between the bacterial adhesin Intimin and Tir (Translocated intimin receptor), a type 3 secretion system effector protein. Intimin-mediated clustering of Tir triggers actin polymerisation, leading to pedestal-like structures at bacterial attachment sites. Here we show that GBP1 is recruited to actin pedestals in human cells infected with EPEC and EHEC in vitro and mouse colonocytes infected with the EPEC-like murine pathogen Citrobacter rodentium in vivo . GBP1-dependent caspase-4 trafficking to these sites leads to pyroptosis and IL-18 release. To dissect the mechanism of GBP1 trafficking, we engineered a chimeric receptor (FcγR-Tir) by combining the intracellular signalling domain of Tir and the extracellular ligand-binding domain of the Fcγ receptor. Clustering of FcγR-Tir with IgG-coated beads produced 'sterile' actin-rich pedestals that were sufficient to recruit GBP1 independently of bacteria. Our findings reveal that cytosolic GBP1 is mobilised to sites of pathogen-induced actin remodelling independently of LPS. We establish that GBP1 not only operates as a pattern-recognition receptor but also orchestrates effector-triggered immunity against pathogens that hijack the actin cytoskeleton.

DOI: https://doi.org/10.1101/2025.09.25.678451

bioRxiv. 2025 Sep 27. pii: 2025.09.26.678815. [Epub ahead of print]

Epithelial cell fusion is required for tissue repair following UV-A irradiation.

Minqi Shen, Lillie G Mitchell, Lydia W Boer, Vicki P Losick.

Cell cycle-dependent and independent mechanisms lead to the generation of mononucleated and multinucleated, polyploid cells. The more than doubling of a cell's nuclear genome by endoreplication has been found to be an adaptation to genotoxic stress, enabling cell survival despite DNA damage. However, it remains unknown whether cells that increase ploidy via multinucleation also arise in response to genotoxic stress. Here, we use ultraviolet light A (UV-A) to induce permanent DNA damage in cells within the adult fruit fly epithelium. UV-A irradiation causes an injury-like response where giant multinucleated, polyploid cells arise following cell death. The epithelial cells undergo endoreplication, which is required to restore tissue mass, but is surprisingly dispensable for tissue repair. UV-A irradiation also induces cell fusion, which generates multinucleated cells that encompass almost the entire epithelial area post injury. Cell fusion can be inhibited by expression of a dominant negative Rac or Cdc42 GTPase, which then blocks epithelial tissue repair post irradiation. Apoptotic nuclei were detected at the site of cell junction breakdown suggesting that apoptosis itself or an apoptotic signal is required for polyploidization in this model. Expression of the effector caspase inhibitor, p35, led to inhibition of apoptosis, the endocycle, and cell fusion post UV-A. Therefore, we have discovered that caspase activation is necessary for polyploidization post injury and enhancing cell ploidy via multinucleation is another strategy to enable cell survival and tissue repair following genotoxic stress.
Significance Statement: Polyploid cells are life's stress responders as the more than doubling of a cell's genome has been shown to enable resistance to genotoxic stress. Cells are exposed to various sources of genotoxic stress, including from ultraviolet light. Here we find that ultraviolet light induces DNA damage causing apoptosis and the subsequent generation of giant, multinucleated polyploid cells in the fruit fly epithelium. Unlike in other models studied to date, cell fusion is the predominant response to genotoxic stress and appears to be essential for tissue repair. This study also determines that polyploidization post UV stress is dependent on caspase activation, suggesting a conserved mechanism to initiate cellular multinucleation both in development as well as in response to life's stressors.

DOI: https://doi.org/10.1101/2025.09.26.678815