bims-cediti 2025-08-03 papers

bims-cediti

Biomed News

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

Issue of 2025–08–03
nine papers selected by
Kateryna Shkarina, Universität Bonn

The Hippo pathway kinase MST1 mediates a feedback loop to maintain NLRP3 inflammasome homeostasis.
Oropouche virus infection induces pyroptosis in human THP-1 macrophages.
Optimizing PDIA1 Inhibition as a Strategy to Inhibit NLRP3 Inflammasome Activation and Activity.
Caspase-14-like Proteases: An Epidermal Caspase and Its Evolutionarily Ancient Relatives.
The vaccinia virus protein, C16, promotes the ubiquitylation and relocalization of the antiviral E3 ubiquitin-ligase, TRIM25.
Early Antibody-Mediated Immunity to Tuberculosis in Mice Requires NLRP3.
Epithelial cell membrane perforation induces allergic airway inflammation.
RIPK1 S213E mutant suppresses RIPK1-dependent cell death by preventing interactions with RIPK3 and CASP8.
Apoptotic cells promote circulating tumor cell survival and metastasis.

Cell Rep. 2025 Jul 26. pii: S2211-1247(25)00847-2. [Epub ahead of print]44(8): 116076

The Hippo pathway kinase MST1 mediates a feedback loop to maintain NLRP3 inflammasome homeostasis.

Xiawei Huang, Jiahui Wang, Yao Liu, Huimin Pan, Kewei Zheng, Bo Liu.

  Inflammasomes play pivotal roles in inflammatory responses. However, their activity must be tightly controlled to prevent overactivation and subsequent inflammatory diseases. Negative feedback loops represent a general mechanism to maintain signaling homeostasis, yet the mechanisms by which inflammasomes employ this process to prevent overactivation remain poorly understood. Here, we identify a negative feedback loop mediated by the Hippo pathway kinase mammalian Ste20-like kinase 1 (MST1) that prevents hyperactivation of the NLRP3 inflammasome. Mechanistically, NLRP3 inflammasome activation induces caspase-1-dependent cleavage of MST1 on its inhibitory linker region, resulting in enhanced kinase activity. The enhanced MST1 phosphorylates the inflammasome adaptor protein ASC at serine 58, disrupting ASC oligomerization and thereby attenuating inflammasome assembly. Notably, staurosporine (STS), a chemical inducer of MST1 cleavage, mitigates inflammation and tissue damage in a lipopolysaccharide (LPS)-induced sepsis mouse model. These findings reveal a negative feedback mechanism for maintaining inflammatory homeostasis and highlight MST1 cleavage as a potential therapeutic target for controlling inflammation.

Keywords:  ASC; CP: Immunology; CP: Molecular biology; Hippo pathway; MST1/2; NLRP3; caspase-1; endoproteolytic cleavage; feedback loop; inflammasome; phosphorylation

DOI:  https://doi.org/10.1016/j.celrep.2025.116076
Virology. 2025 Jul 21. pii: S0042-6822(25)00243-0. [Epub ahead of print]611 110630

Oropouche virus infection induces pyroptosis in human THP-1 macrophages.

Eduardo Jurado-Cobena, Cigdem Alkan, Tetsuro Ikegami.

  Oropouche fever, an emerging zoonotic viral disease in Central and South America, is caused by Oropouche virus (OROV). While typically self-limiting, severe complications such as aseptic meningoencephalitis, miscarriage, and neonatal malformations can occur. Macrophages are critical in host defense, but the pathological mechanisms underlying OROV infection remain unclear. IL-1β, a key pro-inflammatory cytokine, plays a central role in the febrile response and is regulated by inflammasomes, such as NLRP3. This study investigates NLRP3-mediated IL-1β maturation and pyroptotic cell death in OROV-infected human THP-1 macrophages. Our findings reveal that macrophages, but not monocytes, are permissive to OROV infection and undergo pyroptosis through the activation of caspases-1, -3, and -8, resulting in the cleavage of GSDMD and GSDME, and the release of IL-1β. Interestingly, the cleaved form of GSDMD was predominantly the inactive p23 fragment. Furthermore, NLRP3-deficient macrophages failed to activate caspases, cleave Gasdermins, or produce IL-1β upon infection. These results demonstrate that OROV infection triggers NLRP3-mediated IL-1β maturation and release via pyroptosis in macrophages, underscoring their potential role in OROV pathogenesis.

Keywords:  Gasdermin D; Gasdermin E; Interleukin-1β; Macrophage; NLRP3; Oropouche virus; Pyroptosis

DOI:  https://doi.org/10.1016/j.virol.2025.110630
ACS Chem Biol. 2025 Jul 29.

Optimizing PDIA1 Inhibition as a Strategy to Inhibit NLRP3 Inflammasome Activation and Activity.

Chavin Buasakdi, Caroline R Stanton, Prerona Bora, Priyadarshini Chatterjee, Michael J Bollong, R Luke Wiseman.

The NLRP3 inflammasome is a protein complex that promotes pro-inflammatory signaling as part of the innate immune response. Hyperactivation of the NLRP3 inflammasome has been implicated in many inflammatory and neurodegenerative diseases, leading to significant effort in developing strategies to limit its activation to intervene in these disorders. We previously showed that pharmacologic inhibition of endoplasmic reticulum (ER)-localized protein disulfide isomerase PDIA1 suppresses NLRP3 activation and activity, identifying PDIA1 as a potential therapeutic target to mitigate hyperactive NLRP3 activity. Herein, we screen PDIA1 inhibitors to identify highly potent compounds, including P1 and PACMA31, that pharmacologically target PDIA1 and block NLRP3 inflammasome assembly and activity. While sustained treatment with these PDIA1 inhibitors reduces THP1 viability, we show that acute treatment with these compounds is sufficient to both fully modify PDIA1 and inhibit NLRP3 inflammasome activity independent of any overt cellular toxicity. These results establish a treatment paradigm that can be exploited to develop highly selective PDIA1 inhibitors to mitigate hyperactive NLRP3 inflammasome activity implicated in etiologically diverse diseases.

DOI: https://doi.org/10.1021/acschembio.5c00221
Biomolecules. 2025 Jun 22. pii: 913. [Epub ahead of print]15(7):

Caspase-14-like Proteases: An Epidermal Caspase and Its Evolutionarily Ancient Relatives.

Leopold Eckhart, Attila Placido Sachslehner, Julia Steinbinder, Heinz Fischer.

  Caspases are a family of cysteine-dependent aspartate-directed proteases implicated in programmed cell death. Humans have eleven proteolytically active caspases, namely caspase-1 through -10 and caspase-14. The latter is expressed exclusively in epithelial cells and constitutively resides in its active form in the cornified layer of the human epidermis. Molecular phylogenetics has revealed that caspase-14 belongs to a subfamily of caspases, which also includes caspase-15 and -16. The latter are evolutionarily more ancient than caspase-14 and have been lost in the phylogenetic lineage leading to humans. Here, we review the molecular properties, the species distributions, and the biological roles of caspase-14-like proteases in amniotes. In contrast to the prodomain-less caspase-14, caspase-15 contains a prodomain that is predicted to assume a pyrin fold, and caspase-16 features a prodomain with unique sequence similarity to the catalytic domain. Gene knockout in mice, evolutionary gene loss in aquatic mammals and the association of human CASP14 mutations with ichthyosis indicate that caspase-14 is associated with the barrier function of mammalian skin. Caspase-15 is able to induce apoptosis in cell culture, but its role in vivo and the role of caspase-16 are currently unknown. We propose directions for research to further characterize caspase-14-like proteases.

Keywords:  apoptosis; caspase; cornification; evolution; gene duplication; inflammasome; keratinocyte; protein domain; pyrin; pyroptosis

DOI:  https://doi.org/10.3390/biom15070913
J Virol. 2025 Jul 28. e0089825

The vaccinia virus protein, C16, promotes the ubiquitylation and relocalization of the antiviral E3 ubiquitin-ligase, TRIM25.

Jianing Dong, Shu Yue Luo, Summer Smyth, Grace Melvie, Olivier Julien, Robert J Ingham.

  Poxviruses co-opt the ubiquitin (Ub)-proteasome system (UPS) to facilitate virus replication, evade the innate immune response, and block programmed cell death of infected cells. Moreover, the UPS is an integral component of innate immune signaling pathways used by the host to respond to infection. To further elucidate how the UPS is engaged early during poxvirus infection, we quantified viral and cellular peptides with a Ub remnant motif (diGly peptides) from lysates of uninfected and vaccinia virus Copenhagen strain (VACV-Cop)-infected HeLa cells. Of note, we identified several ubiquitylated peptides from the cellular antiviral protein, TRIM25, that were enriched for, or exclusively found, in VACV-Cop-infected cells. TRIM25 is an E3 ligase for Ub and the Ub-like protein, ISG15, and TRIM25 performs several functions including activating the type I interferon response. Higher-molecular weight, ubiquitylated TRIM25 species were evident as early as 1 h post-infection of HeLa cells with VACV-Cop, and they persisted throughout infection. Proteasomal or lysosomal degradation did not appear to be a major consequence of this ubiquitylation; however, TRIM25 ubiquitylation correlated with its relocalization to punctate structures in infected cells. C16, a Bcl-2 family-like protein encoded by identical genes on both arms of the VACV-Cop genome, was both necessary and sufficient to promote TRIM25 ubiquitylation and relocalization. These phenomena were not evident in cells infected with Orthopoxviruses lacking the genes encoding for C16. We postulate that the ubiquitylation and/or relocalization of TRIM25 induced by C16 could represent a novel mechanism for poxviruses to subvert the host antiviral response.IMPORTANCEUbiquitylation is a versatile post-translational modification that is required for poxviruses to replicate their genomes and evade host cell defenses to infection. At the same time, both degradative and non-degradative protein ubiquitylation are critical components of the innate and adaptive immune responses to infection. In this study, we opted for a proteomics approach to examine changes in protein ubiquitylation early after vaccinia virus infection with the goal of identifying novel ways by which ubiquitylation is exploited during infection. We demonstrate that many Orthopoxviruses utilize the Bcl-2 family-like protein C16 to promote the ubiquitylation and relocalization of the cellular E3 ubiquitin/ISG15-ligase, TRIM25, which we hypothesize represents a novel strategy by which these viruses evade the host cell antiviral response. Moreover, our findings hint that Orthopoxviruses may also have C16-independent strategies to interfere with the function of TRIM25.

Keywords:  E3-ubiquitin ligase; TRIM25; diGly; poxvirus; ubiquitylation; vaccinia virus

DOI:  https://doi.org/10.1128/jvi.00898-25
bioRxiv. 2025 Jul 18. pii: 2025.07.18.665318. [Epub ahead of print]

Early Antibody-Mediated Immunity to Tuberculosis in Mice Requires NLRP3.

Rania Bouzeyen, Nyaradzai Sithole, Avia Watson, Lilach Abramovitz, Katya Rakayev, Adam Fillion, Tessa Dickson, Paul A MacAry, Patricia A Darrah, Robert A Seder, Natalia T Freund, Babak Javid.

While antibodies have emerged as potential mediators of protective immunity against Mycobacterium tuberculosis (Mtb), their mechanisms of action remain incompletely understood. Here, we demonstrate that immune complexes of Mtb and monoclonal antibodies targeting the Mtb phosphate transporter subunit PstS1 robustly activate the NLRP3 inflammasome in human and murine macrophages, leading to enhanced interleukin-1β secretion. Surprisingly, antibody-mediated inflammasome activation occurred independently of cell-surface Fcγ receptors, as confirmed using Fc-domain glycosylation mutant mAbs and macrophages from Fcγ receptor-deficient mice. Crucially, NLRP3 is indispensable for early antibody-mediated protection in vivo, as both pharmacological inhibition, and genetic deletion of NLRP3 completely abolished protective effects of PstS1-specific antibodies in Mtb-infected mice. This mechanism extends beyond monoclonal antibodies, as polyclonal sera from intravenously BCG-immunized rhesus macaques also required NLRP3 for protective efficacy. Our findings reveal a previously unrecognized mechanism by which Mtb-specific antibodies enhance host defense through inflammasome activation, potentially informing novel approaches for tuberculosis vaccine development.

DOI: https://doi.org/10.1101/2025.07.18.665318
Nature. 2025 Jul 30.

Epithelial cell membrane perforation induces allergic airway inflammation.

Kejian Shi, Yao Lv, Chunqiu Zhao, Huan Zeng, Yeqiong Wang, Yuxuan Liu, Lin Li, She Chen, Pu Gao, Feng Shao, Mo Xu.

Allergens that induce allergic airway inflammation are highly diverse, but they commonly activate type 2 immune responses1,2. Airway epithelial cells are crucial in allergen sensing3-5. However, the shared features among diverse allergens that elicit similar innate responses, and their epithelial detection mechanisms, remain poorly defined1,2,6-9. Here we identify pore-forming proteins as one of the common stimuli of allergic airway inflammation and reveal their immune-activation mechanisms. Using the prevalent mould allergen Alternaria alternata as a model, we established an in vitro system to investigate type 2 innate immune sensing. A six-step biochemical fractionation identified Aeg-S and Aeg-L as the core immune-stimulatory components. Biochemical reconstitution and cryo-electron microscopy reveal that these proteins form 16- to 20-mer transmembrane pore complexes. Their cooperative perforation acts as a bona fide type 2 immune adjuvant to support antigen-specific T helper 2 and immunoglobulin E responses. Genetically engineered A. alternata strains that lack pore-forming activity do not induce allergic responses in mice. Furthermore, pore-forming proteins from various species, despite structural and membrane target differences, are sufficient to trigger respiratory allergies. Perforations in airway epithelial cells initiate allergic responses through two mechanisms: one triggers IL-33 release, and the other involves Ca2+ influx, which activates MAPK signalling and type 2 inflammatory gene expression. These findings provide insight into how type 2 immune responses detect common perturbations caused by structurally diverse stimuli. Targeting downstream signalling of epithelial perforation may open new avenues for treating respiratory allergies.

DOI: https://doi.org/10.1038/s41586-025-09331-1
Cell Death Discov. 2025 Jul 25. 11(1): 345

RIPK1 S213E mutant suppresses RIPK1-dependent cell death by preventing interactions with RIPK3 and CASP8.

Ning Nan, Hong Hu, Xinxin Zhu, Jia Liu, Feiyang Yuan, Zhijie Li, Huayi Wang.

RIPK1 (Receptor-interacting serine/threonine-protein kinase 1) is fundamental in regulating cell proliferation, programmed cell death, and inflammation. Within the TNF (tumor necrosis factor) signaling pathway, the kinase activity of RIPK1 is essential for determining cellular fate, promoting either apoptosis or necroptosis. Mutations disrupting RIPK1 kinase activity significantly impact cellular fate decisions, highlighting its importance in the TNF signaling cascade. This study generated and characterized a novel mutation of human RIPK1, S213E that exhibits unique inhibitory properties. Although located in the kinase domain, the S213E mutation disrupts RIPK1 homodimerization and its interactions with downstream effectors, such as RIPK3, without directly suppressing RIPK1 kinase activity. These findings indicate that the S213E mutation converts RIPK1 into a super-autoinhibitory state, effectively isolating it from downstream effectors involved in both apoptosis and necroptosis.

DOI: https://doi.org/10.1038/s41420-025-02647-x
Commun Biol. 2025 Jul 29. 8(1): 1121

Apoptotic cells promote circulating tumor cell survival and metastasis.

Cassidy E Hagan, Valerie M Sheehan, Charles M Rezanka, Meijie A Li, Laura Martínez-Escardó, Kirsteen J Campbell, Annelise G Snyder, Mark Headley, Andrew Oberst.

During tumor progression and especially following cytotoxic therapy, cell death of both tumor and stromal cells is widespread. Despite clinical observations that high levels of apoptotic cells correlate with poorer patient outcomes, the physiological effects of dying cells on tumor progression remain incompletely understood. Here, we report that circulating apoptotic cells robustly enhance tumor cell metastasis to the lungs. Using intravenous metastasis models, we observed that the presence of apoptotic cells, but not cells dying by other mechanisms, supports circulating tumor cell (CTC) survival following arrest in the lung vasculature. Apoptotic cells promote CTC survival by recruiting platelets to the forming metastatic niche. Apoptotic cells externalize the phospholipid phosphatidylserine to the outer leaflet of the plasma membrane, which we found increased the activity of the coagulation initiator Tissue Factor, thereby triggering the formation of platelet clots that protect proximal CTCs. Inhibiting the ability of apoptotic cells to induce coagulation by knocking out Tissue Factor, blocking phosphatidylserine, or administering the anticoagulant heparin abrogated the pro-metastatic effect of apoptotic cells. This work demonstrates a previously unappreciated role for apoptotic cells in facilitating metastasis by establishing CTC-supportive emboli, and suggests points of intervention that may reduce the pro-metastatic effect of apoptotic cells.

DOI: https://doi.org/10.1038/s42003-025-08541-7