bims-cediti 2025-10-12 papers

Issue of 2025–10–12
four papers selected by
Kateryna Shkarina, Universität Bonn

Cell Death Dis. 2025 Oct 06. 16(1): 681

ALIX mediates reversible gasdermin-D pore formation via the endosomal pathway to limit pyroptosis by active membrane repair.

Sylvia Otchere, Prafulla Shrestha, Himesh N Parmar, Jadyn F Perry, Brittany L Hofmeister, Michelle Steyn, Radhey S Kaushik, Adam D Hoppe, Natalie W Thiex, Ryan L Hanson, Jaime Lopez-Mosqueda, Gergely Imre.

Pyroptosis is a form of regulatory cell death characterized by membrane rupture and release of pro-inflammatory signals. In pyroptosis, Caspase-1 activation leads to the cleavage of gasdermin-D (GSDMD). Upon cleavage, GSDMD's N-terminal (N-GSDMD) fragments insert into the plasma membrane, oligomerize, and form pores. The molecular details that define whether GSDMD pore formation results in cell death or survival are largely unknown. In this study, we show that a shorter duration of membrane N-GSDMD pores (t ≤ 2 h), along with associated membrane permeability does not harm cellular viability. We demonstrate that N-GSDMD is removed, and membrane integrity is restored if the pyroptotic stimulus is washed out within 1 hour. In contrast, longer duration of N-GSDMD pore formation leads to large-scale membrane damage and cell death. Using a selective dynamin inhibitor and confocal microscopy, to co-label N-terminal GSDMD (N-GSDMD) and the early endosomal marker EEA1, we demonstrate that N-GSDMD is cleared from the plasma membrane via the endosomal pathway. Through stable ALIX knockdown and overexpression approaches, we further show that ALIX, a key accessory protein of the ESCRT machinery, regulates N-GSDMD pore dynamics by promoting its removal and facilitating membrane repair via N-GSDMD internalization. In summary, we show that the duration of N-GSDMD membrane pores is a decisive factor and ALIX-dependent mechanism facilitates N-GSDMD removal and restores membrane integrity. The identification of these factors can open the development of new therapeutic strategies in chronic inflammatory conditions by bolstering the cell's inherent self-healing potential.

DOI: https://doi.org/10.1038/s41419-025-07998-y

Cell Mol Immunol. 2025 Oct 09.

Molecular mechanisms and regulation of inflammasome activation and signaling: sensing of pathogens and damage molecular patterns.

Sagar R Dubey, Cynthia Turnbull, Abhimanu Pandey, Anyang Zhao, Melan Kurera, Radhwan Al-Zidan, Cheng Shen, Manjul Gautam, Shreya Mahajan, Poonam S Jadhav, Aritra Ghosh, Chinh Ngo, Si Ming Man.

The inflammasome is an inflammatory signaling protein complex comprising a sensor protein, the adaptor protein ASC, and the cysteine protease caspase-1. Inflammasome sensor proteins are activated by microbial molecular patterns, endogenous self-derived damage signals, or exogenous environmental danger signals. Multiple inflammasomes that differ in their mechanisms of action and structural composition have been identified. The best characterized are the canonical NLRP1, NLRP3, NAIP-NLRC4, AIM2, and Pyrin inflammasomes and the noncanonical inflammasomes activated by caspase-4, caspase-5 or caspase-11. The lesser known inflammasomes are the NLRP6, NLRP7, NLRP9, NLRP10, NLRP12, CARD8, and MxA inflammasomes. Following inflammasome assembly, caspase-1 promotes the secretion of the proinflammatory cytokines IL-1β and IL-18, and pyroptosis is mediated by the membrane-disrupting proteins gasdermin D and ninjurin-1. These functional activities control innate and adaptive immune responses and the initiation, development, and progression of autoinflammation, cancer, infectious diseases, and neurodegenerative diseases. Understanding how inflammasomes respond to pathogens and sterile signals has refined our view of innate immunity and offered new therapeutic targets. In this review, we present a comprehensive overview of inflammasomes with an emphasis on the mechanistic principles that govern inflammasome formation. We also discuss the contributions of inflammasome activation to health and disease.

Keywords: GSDMD; Infection; Interferons; LPS; NINJ1; Pattern-recognition receptors

DOI: https://doi.org/10.1038/s41423-025-01354-y

Infect Immun. 2025 Oct 07. e0047925

Induced necroptosis limits Toxoplasma gondii replication in a RIPK3/MLKL-dependent manner.

Billy J Erazo, Laura J Knoll.

Toxoplasma gondii is an obligate intracellular parasite capable of subverting host defenses to establish infection. Necroptosis, a lytic pro-inflammatory form of programed cell death, has emerged as a host defense mechanism against intracellular pathogens. However, its relevance in controlling T. gondii replication remains unclear. Here, we investigated the role of necroptosis in limiting T. gondii replication using bone marrow-derived macrophages (BMDMs) deficient in key necroptotic mediators, RIPK3 and MLKL. We demonstrate that under naïve conditions, T. gondii replication proceeds unimpeded in RIPK3-/- and MLKL-/- BMDMs. However, co-treatment with TNF-α and the pan-caspase inhibitor Z-VAD-FMK, conditions that promote necroptosis, significantly reduced parasite replication in wild-type BMDMs but not in those lacking RIPK3 or MLKL. This suppression was dependent on RIPK1 activity, as pharmacological inhibition with Necrostatin-1 abrogated the effect. We further confirmed that TNF-α and Z-VAD-FMK treatment induced necroptotic cell death characterized by loss of plasma membrane integrity, both of which were absent in RIPK3-/- and MLKL-/- cells. These findings establish that the activation of necroptosis can effectively limit T. gondii replication in BMDMs and underscore the importance of RIPK1-RIPK3-MLKL signaling in mounting a cell-intrinsic immune defense. Our study provides new insight into the functional capacity of necroptosis in restricting intracellular parasites and highlights its potential as a therapeutic target in toxoplasmosis.

Keywords: Toxoplasma gondii; apoptosis; necroptosis; programmed cell death

DOI: https://doi.org/10.1128/iai.00479-25

Annu Rev Pathol. 2025 Oct 09.

Gasdermins, Executors of Pyroptosis: A Decade in Perspective.

Bowen Zhou, Derek Abbott.

Pyroptosis is a molecularly defined pathway of cell death and lysis relying on formation of membrane pores by the family of gasdermin proteins. Since the characterization of prototypical gasdermin D in 2015, intense effort in the past decade has shed light on protease-dependent activation of these agents of cellular demise in human health and disease, although cell death-independent functions do exist. Numerous regulatory mechanisms ranging from posttranslational modification, control of expression, and overlap in activation systems have been described, but pharmacologic control of gasdermins is still in its infancy. Thus, gasdermin-specific targeting in disease has not yet been achieved outside of a few select cases. This review summarizes these findings broadly from a perspective of biological mechanisms and highlights the forthcoming challenges hindering bench-to-bedside adoption of this knowledge.

DOI: https://doi.org/10.1146/annurev-pathmechdis-042624-121548