bims-cediti 2025-07-27 papers

bims-cediti

Biomed News

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

Issue of 2025–07–27
eight papers selected by
Kateryna Shkarina, Universität Bonn

Three decades of caspases and RIPKs in life and death.
Gasdermin C cleavage by Cathepsin S modulates Rab7 vesicles in intestinal epithelial cells to amplify anti-helminth immunity.
Pseudorabies virus induces natural killer cell depletion by GSDMD-mediated inflammation and pyroptosis to promote infection and lung injury.
Disrupting membranes, controlling cell fate: the role of pore-forming proteins in cell death and therapy.
Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections.
Protein Kinase C promotes peroxisome biogenesis and peroxisome-endoplasmic reticulum interaction.
High-throughput screening system for immunogenic cell death inducers using artificial intelligence-based real-time image analysis.
MyD88 polymerization and association to cellular membranes in a yeast heterologous model.

Hum Mol Genet. 2025 Jul 25. pii: ddaf106. [Epub ahead of print]

Three decades of caspases and RIPKs in life and death.

R K Subbarao Malireddi, Thirumala-Devi Kanneganti.

  Caspases and RIPKs are critical regulators of life and death. These molecules have roles in innate immunity and cell death that drive host defense, development, and tumor immunity, but their activation can also contribute to aberrant inflammation and inflammatory disease. This review revisits three decades of genetic studies that have elucidated the critical functions of caspases and RIPKs, synthesizing seminal findings in development, lytic cell death pathways, inflammation, disease pathology, and therapeutic innovation. These studies have led to the paradigm-shifting concept of PANoptosis, defined as an innate immune, inflammatory cell death pathway initiated by innate immune sensors and driven by caspases and RIPKs through PANoptosome complexes. PANoptosis can occur in response to pathogens, pathogen- and damage-associated molecular patterns, homeostatic alterations, cytokines, and the lytic cell death of surrounding cells. Caspase-8 has emerged as a critical core component of PANoptosomes, with other caspases and RIPKs also being key to the molecular activation of PANoptosis. Further genetic studies have established the significance of caspases and RIPKs, including their role in PANoptosis, across the disease spectrum, in infections, inflammatory conditions, cytokine storm, and cancer. Collectively, genetic and biochemical evidence suggests that targeting PANoptosome pathway molecules, including innate immune sensors, caspases, and RIPKs, provides a promising therapeutic strategy for a wide range of conditions, such as neurodegeneration, metabolic disorders, cancers, and chronic inflammatory or autoimmune diseases.

Keywords:  AIM2; IRFs; MLKL; NLRs; PANoptosis; PANoptosome; RIPK1; RIPK3; TLRs; ZBP1; apoptosis; caspase; cell death; development; embryogenesis; gasdermin D; gasdermin E; genetics; inflammasome; inflammation; innate immunity; innate sensors; necroptosis; pyroptosis

DOI:  https://doi.org/10.1093/hmg/ddaf106
Immunity. 2025 Jul 16. pii: S1074-7613(25)00287-0. [Epub ahead of print]

Gasdermin C cleavage by Cathepsin S modulates Rab7 vesicles in intestinal epithelial cells to amplify anti-helminth immunity.

Surya P Pandey, Donghui Yang, Lee Hedden, Colin R Laughlin, Weihong Wang, Ariadna S Soto, Halah Winner, Luzmariel Medina Sanchez, Edith E Campana, Clarisse Engl, Yanlin Zeng, Mohit Rana, Lauren Van Der Kraak, Mackenzie J Bender, Joshua Prokopec, Julia M Ferrick, Xinan Meng, Erica Fong, Mai Sun, Steven J Mullett, Matthew MacDonald, Stacy L Gelhaus, Simon C Watkins, Marlies Meisel, Jakob von Moltke, Suhong Xu, Yi-Nan Gong, Reinhard Hinterleitner.

  Gasdermins are canonically associated with plasma membrane pore formation and lytic cell death. Gasdermin C (GsdmC), predominantly expressed in intestinal epithelial cells (IECs), seems to operate independently of these canonical roles. Here, we show that activated GsdmC is increased in response to type 2 immunity in the gut, driven by Cathepsin S (CTSS)-mediated cleavage. Although IEC cell death is not the main consequence of GsdmC cleavage, inserting a single amino acid (aa) within the lipid-binding motif to match that of the other gasdermins enhanced GsdmC oligomerization and increased GsdmC-mediated cell death. Mechanistically, instead of localizing to the plasma membrane, we showed that cleaved GsdmC targeted Rab7+ vesicles, such as late endosomes. This modulated lipid droplet accumulation, which promoted goblet cell hyperplasia and type 2 immune responses. These findings demonstrate how GsdmC in IEC protects against helminth infection and expands the role of gasdermins beyond cell death and cytokine release.

Keywords:  Cathepsin S; Gasdermin C; Rab7; helminth; intestinal epithelial cells; protist; type 2 immune

DOI:  https://doi.org/10.1016/j.immuni.2025.06.018
J Virol. 2025 Jul 24. e0041525

Pseudorabies virus induces natural killer cell depletion by GSDMD-mediated inflammation and pyroptosis to promote infection and lung injury.

Jing Chen, Guangming Zhao, Yi Yang, Yinhui Li, Yu Song, Daxia Li, Qian Du, Dewen Tong, Yong Huang.

  Pseudorabies virus (PRV) infection induces a hyperinflammatory response to promote inflammatory injury in multiple tissues. However, the relative mechanism remains elusive. Herein, we first confirmed that PRV infection could trigger pyroptosis to cause lung injury, evidenced by the increased release of pro-inflammatory cytokines and lactate dehydrogenase (LDH) in lung tissue of infected piglets and mice. Subsequently, we observed that PRV-induced lung lesions and mortality were improved in Gsdmd-/- mice rather than in Ripk3-/- mice. The number of NK cells was markedly higher in Gsdmd-/- mice than in WT mice. Based on this finding, refilling NK cells could significantly alleviate the replication of PRV in the lungs of mice and alleviate lung injury caused by PRV infection, whereas depletion of NK cells aggravated PRV infection and led to severe lung lesions. Notably, gasdermin D (GSDMD) deficiency could reduce the production of tumor necrosis factor-α (TNF-α) positive macrophages and the depletion of NK cells induced by PRV infection to alleviate the pathogenicity of PRV, while TNF-α neutralizing antibody could also reduce the PRV-induced NK cell depletion to alleviate the pathogenicity of PRV. Ultimately, we found that necrosulfonamide (NSA) showed a good protective effect on PRV-infected mice and had good anti-PRV activity in vivo. Collectively, our findings illuminate a new regulatory mechanism by which PRV infection induces NK cell depletion to weaken the antiviral ability of the host to promote virus replication and activate GSDMD-mediated pyroptosis in lung tissue, leading to severer lung injury, and NSA is expected to be a candidate agent for the prevention and control of PRV infection.IMPORTANCENecroptosis and pyroptosis are the most common regulated necrotic cell death pathways in various pathogenic infection-induced tissue damage. Herein, we found that gasdermin D (GSDMD)-mediated pyroptosis is a critical cell death pathway in pseudorabies virus (PRV)-induced lung inflammatory injury rather than receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis. PRV infection induces NK cell depletion to weaken the antiviral ability of the host to promote viral replication. GSDMD deficiency can reduce the depletion of NK cells induced by PRV infection by reducing the production of tumor necrosis factor-α (TNF-α)-positive macrophages, thereby attenuating lung tissue lesions in PRV-infected mice. Whereas the use of necrosulfonamide (NSA) showed a good protective effect on PRV-infected mice. This study reveals that PRV infection can excessively activate macrophages to secrete more TNF-α to induce NK cell depletion to facilitate PRV infection and aggravate viral pathogenicity, and clarifies the roles of GSDMD in modulating macrophage activity and NK cell death, and also provides an effective inhibitor for use against PRV infection.

Keywords:  NK cell; lung injury; pseudorabies virus

DOI:  https://doi.org/10.1128/jvi.00415-25
Apoptosis. 2025 Jul 21.

Disrupting membranes, controlling cell fate: the role of pore-forming proteins in cell death and therapy.

Sonia Iranpour, Maryam Arif, Eva Szegezdi.

  Pore-forming proteins (PFPs), characterized by their ability to form pores or disrupt membranes are now recognized as key executioners of cell death, either as effectors of the immune system (non-cell-autonomous function), or of regulated cell death programs (cell autonomous function). To perforate membranes, most PFPs transition from water-soluble monomers or oligomers into multimeric and often supramolecular complexes, a process achieved via substantial structural transition of the PFP. Although they share the general ability to perforate cellular or intracellular membranes, PFPs differ in their membrane-binding preferences, the structural and functional characteristics of the pores they form (such as pore size, pore structure and ability to trigger membrane rupture) and the cell death mechanism they induce or execute. Herein, we review the specific traits of all key human PFPs, including their membrane specificity, regulation of their activity and the structure of the membrane pores they form, followed by insights into the therapeutic potential of PFPs and harnessing their abilities for cancer therapy.

Keywords:  Cancer therapy; Gasdermin; Granulysin; Mixed lineage kinase domain-like pseudokinase (MLKL); Ninjurin-1; Perforin; Pore-forming proteins (PFP); Regulated cell death

DOI:  https://doi.org/10.1007/s10495-025-02133-w
Immunity. 2025 Jul 12. pii: S1074-7613(25)00286-9. [Epub ahead of print]

Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections.

Marco Di Gioia, Valentina Poli, Piao J Tan, Roberto Spreafico, Anne Chu, Alex G Cuenca, Zhongyang Wu, Mehdi Benamar, Laura Pandolfi, Federica Meloni, Fatemeh Askarian, Jason Hsiao, Elizaveata Borroum, Victor Nizet, Philip L S M Gordts, Joseph L Witztum, Talal A Chatila, Janet Chou, Xu Zhou, James R Springstead, Ivan Zanoni.

  Phagocytes initiate immunity to invading microorganisms by detecting pathogen-associated molecular patterns via pattern recognition receptors. Pathogen encounter and consequent activation of the immune system cause tissue damage and the release of host-derived damage-associated molecular patterns, contributing to shape immunity. However, how self-derived factors are sensed by phagocytes and impact the immune response remains poorly understood. Here, we demonstrated that host-derived oxidized phospholipids (oxPLs) are formed after microbial encounter in both mice and humans. oxPLs exacerbated inflammation without affecting pathogen burden. Mechanistically, oxPLs bound and inhibited AKT, potentiating the methionine cycle and the activity of the epigenetic writer EZH2. EZH2 epigenetically dampened the pluripotent anti-inflammatory cytokine IL-10, contributing to the death of the host. Overall, we found that host-derived oxPLs set the balance between protective and detrimental antimicrobial responses and that they can be prophylactically or therapeutically targeted to protect the host against deranged inflammation and immunopathology.

Keywords:  ARDS; DAMP; PAMP; PRR; damage-associated molecular pattern; epigenetic; macrophages; pathogen-associated molecular pattern; pattern recognition receptor; sepsis

DOI:  https://doi.org/10.1016/j.immuni.2025.06.017
J Cell Biol. 2025 Sep 01. pii: e202505040. [Epub ahead of print]224(9):

Protein Kinase C promotes peroxisome biogenesis and peroxisome-endoplasmic reticulum interaction.

Anya Borisyuk, Charlotte Howman, Sundararaghavan Pattabiraman, Daniel Kaganovich, Triana Amen.

Peroxisomes carry out a diverse set of metabolic functions, including oxidation of very long-chain fatty acids, degradation of D-amino acids and hydrogen peroxide, and bile acid production. Many of these functions are upregulated on demand; therefore, cells control peroxisome abundance, and by extension peroxisome function, in response to environmental and developmental cues. The mechanisms upregulating peroxisomes in mammalian cells have remained unclear. Here, we identify a signaling regulatory network that coordinates cellular demand for peroxisomes and peroxisome abundance by regulating peroxisome proliferation and interaction with ER. We show that PKC promotes peroxisome PEX11b-dependent formation. PKC activation leads to an increase in peroxisome-ER contact site formation through inactivation of GSK3β. We show that removal of VAPA and VAPB impairs peroxisome biogenesis and PKC regulation. During neuronal differentiation, active PKC leads to a significant increase in peroxisome formation. We propose that peroxisomal regulation by transient PKC activation enables fine-tuned responses to the need for peroxisomal activity.

DOI: https://doi.org/10.1083/jcb.202505040
Comput Biol Med. 2025 Jul 22. pii: S0010-4825(25)01078-9. [Epub ahead of print]196(Pt B): 110727

High-throughput screening system for immunogenic cell death inducers using artificial intelligence-based real-time image analysis.

Eunseo Kim, Donghoon Jang, Minji Kim, Jiwon Heo, Jisoo Shin, Joo-Yoon Chung, Minji Choi, Wen-Hao Yang, Hyungyu Lee, Jong-Ho Cha.

  Immunogenic cell death (ICD) can enhance the immunogenicity of cold tumors, convert them into immune-responsive hot tumors, and improve the efficacy of cancer immunotherapy. Because ICD inducers cause cell swelling, membrane rupture, and the release of damage-associated molecular patterns (DAMPs), effective screening of ICD inducers requires a system capable of rapidly and accurately assessing morphological changes and DAMP dynamics on a large scale, thus highlighting the need for advanced image-processing capabilities. In the present study, we developed an artificial intelligence (AI)-based detector to screen for ICD inducers by identifying the typical morphologies of dying cells undergoing ICD. To enhance the performance, we applied transfer learning from fluorescent markers and fine-tuned the model using differential interference contrast (DIC) images. In addition, model-assisted labeling (MAL) improved annotation efficiency by reducing the need for manual labeling in ICD screening. In a blind test, the AI successfully identified three ICD-inducing agents from eight candidates, which were validated through analyses of cell death type, DAMP release, and immune activation. Our AI-based high-throughput screening (HTS) system efficiently identified ICD candidates using only real-time optical images, thereby significantly reducing the time and resources required for screening. In addition, the system demonstrated the ability to detect subtle morphological differences that are difficult to discern through manual analysis, indicating its potential for ICD prediction as well as for foundational research and broader screening applications.

Keywords:  Cell detection; Damage-associated molecular patterns; High-throughput screening; Immunogenic cell death inducer; Real-time image analysis; Transfer learning; deep learning

DOI:  https://doi.org/10.1016/j.compbiomed.2025.110727
Cell Mol Life Sci. 2025 Jul 25. 82(1): 288

MyD88 polymerization and association to cellular membranes in a yeast heterologous model.

Elba Del Val, Alejandro Fernández-Vega, María Molina, Víctor J Cid.

  MyD88 is a key mediator of Toll-like receptor (TLR) signaling, orchestrating the innate immune response upon stimulation by pathogen-associated molecular patterns (PAMPs). Structurally, MyD88 consists of a Death domain (DD), a 20-amino acid N-terminal extension, and an intermediate (INT) region that connects it to a Toll/Interleukin-1 receptor (TIR) domain. At the core of the signaling complex known as myddosome, MyD88 undergoes homopolymeric interactions to propagate the signal. In this study, we use Saccharomyces cerevisiae as a heterologous model to assess the contribution of individual MyD88 domains to self-interaction and subcellular localization. In yeast, MyD88 localizes to endoplasmic reticulum-mitochondria encounter sites (ERMES). Here, we show that its DD is sufficient for attachment to the ERMES. Deletion of its 20 N-terminal residues increased MyD88 stability, shifting its aggregation pattern from patches to filaments. In contrast, a chimeric MyD88 variant bearing the plasma membrane-binding N-terminal extension of TIRAP, another TLR4-associated myddosome component, exhibited diffuse mitochondrial distribution. Moreover, we found that the ERMES-associated dynamin-like protein Dnm1, involved in mitochondrial fission, played a crucial role in MyD88 expression in yeast. On the other hand, the MyD88 TIR domain alone accumulated at lipid droplets in yeast, and its overexpression led to growth impairment and mitochondrial condensation. These findings suggest that MyD88 association with cellular membranes promotes self-assembly, a process essential for functional TLR signaling. Additionally, we adapted a tripartite GFP system to titrate MyD88 homopolymerization in yeast. Using this system, we observed that the oncogenic L252P mutation significantly reduced MyD88 ability to self-interact.

Keywords:   Saccharomyces cerevisiae ; Humanized yeast; Innate immunity; MyD88; Myddosome; TLR signaling

DOI:  https://doi.org/10.1007/s00018-025-05827-1