bims-cediti 2025-06-29 papers

Issue of 2025–06–29
five papers selected by
Kateryna Shkarina, Universität Bonn

Elife. 2025 Jun 24. pii: RP101990. [Epub ahead of print]14

Hypothermia protects against ventilator-induced lung injury by limiting IL-1β release and NETs formation.

Nobuyuki Nosaka, Vanessa Borges, Daisy Martinon, Timothy R Crother, Moshe Arditi, Kenichi Shimada.

Although mechanical ventilation is a critical intervention for acute respiratory distress syndrome (ARDS), it can trigger an IL-1β-associated complication known as ventilator-induced lung injury. In mice, we found that lipopolysaccharide (LPS) and high-volume ventilation, LPS-HVV, lead to hypoxemia with neutrophil extracellular traps (NETs) formation in the alveoli. Furthermore, Il1r1-/- LPS-HVV mice did not develop hypoxemia and had reduced NETs, indicating that IL-1R1 signaling is important for NETs formation and hypoxemia. Therapeutic hypothermia (TH) is known to reduce the release of inflammatory mediators. In LPS-HVV mice, TH (32°C body temperature) prevented hypoxemia development, reducing albumin leakage, IL-1β, gasdermin D (GSDMD), and NETs formation. We also observed that LPS-primed macrophages, when stimulated at 32°C with ATP or nigericin, release less IL-1β associated with reduced GSDMD cleavage. Thus, hypothermia is an important modulating factor in the NLRP3 inflammasome activation, IL-1β release, and NETs formation, preventing LPS-HVV-induced acute respiratory failure.

Keywords: ARDS; acute; immunology; inflammation; lung; macrophages; mouse; neutrophils; ventilator

DOI: https://doi.org/10.7554/eLife.101990

Cell Metab. 2025 Jun 19. pii: S1550-4131(25)00294-3. [Epub ahead of print]

RIPK1 senses S-adenosylmethionine scarcity to drive cell death and inflammation.

Zezhao Chen, Xiaosong Gu, Hongbo Chen, Huijing Zhang, Jianping Liu, Xiaohua Yang, Yuping Cai, Mengmeng Zhang, Lingjie Yan, Yuanxin Yang, Bing Shan, Zheng-Jiang Zhu, Yixiao Zhang, Jinyang Gu, Daichao Xu.

The capacity of cells to sense and respond to nutrient availability is essential for metabolic homeostasis. Failure in this process may cause cell death and associated diseases. While nutrient sensing in metabolic pathways is well understood, the mechanisms linking nutrient signals to cell death remain unclear. Here, we show that RIPK1, a key mediator of cell death and inflammation, senses methionine and its metabolite, S-adenosylmethionine (SAM), to dictate cell survival and death. SAM-mediated symmetrical dimethylation at RIPK1 Arg606 by PRMT5 functions as a physiological protective brake against RIPK1 activation. Metabolic perturbations, such as methionine restriction or disrupted one-carbon flux, reduce SAM levels and unmask Arg606, promoting RIPK1 self-association and trans-activation, thereby triggering apoptosis and inflammation. Thus, RIPK1 is a physiological SAM sensor linking methionine and one-carbon metabolism to the control of life-or-death decisions. Our findings suggest that RIPK1 could be a potential target for diseases associated with disrupted SAM availability.

Keywords: PRMT5; RIPK1; S-adenosylmethionine; TNF signaling; apoptosis; death domain; inflammation; methionine; methylation; one-carbon metabolism

DOI: https://doi.org/10.1016/j.cmet.2025.05.014

Biomolecules. 2025 Jun 11. pii: 854. [Epub ahead of print]15(6):

The Multifaceted Role of Calcium Signaling in Regulated Necrosis.

Eric Perez-Rivera, Claudia Plasencia, Uris Ros.

Calcium is a versatile ion that regulates diverse intracellular processes, including cell death and survival, cytokine and chemokine production, lipid scrambling, and immune cell activation. In regulated necrosis, an early increase in cytosolic calcium is a hallmark of pathways such as pyroptosis, necroptosis, and ferroptosis, and resembles the calcium surge triggered by pore-forming toxins. The complexity of calcium signaling is orchestrated by specialized channels in various cellular compartments and calcium-binding proteins that respond to localized calcium concentrations. However, the coordination of this intricate code during regulated necrosis and its connections to other calcium-driven processes remains poorly understood. This review provides an overview of the molecular mechanisms of calcium signaling in regulated necrosis, analyzing parallels with pore-forming toxin-mediated membrane damage to uncover nodes that are shared by these seemingly independent pathways. We also discuss advanced techniques for studying calcium dynamics, with high precision, that can be applied to study regulated necrosis. Calcium signaling emerges as a central hub where necrotic cell death pathways converge, shaping the unique signatures of dying cells and influencing their communication with the immune system. This integrated perspective highlights the complex and multifaceted role of calcium in cells and its implications for fundamental cellular processes.

Keywords: calcium signaling; cell death; immune response; membrane damage; necrosis

DOI: https://doi.org/10.3390/biom15060854

bioRxiv. 2025 Apr 09. pii: 2025.04.08.647834. [Epub ahead of print]

Caspase Cleavage of Kaposi Sarcoma-Associated Herpesvirus Proteins: A role for K5 in Preventing Caspase-Mediated Cell Death during Lytic Replication.

Yana Astter, David A Davis, Emma Treco, Prabha Shrestha, Alexandra Stream, Muzammel Haque, Naomi Mulugeta, Robert Yarchoan.

We previously reported that Kaposi sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) acts as a pseudo-substrate for caspases-1 and 3, thereby interfering with their inflammatory and apoptotic activity, respectively. To determine if other KSHV proteins undergo caspase cleavage, we screened the KSHV proteome for potential caspase cleavage sites. Using SitePrediction (SP), 30 KSHV proteins with potential caspase-cleavage sites were identified. Among those with highest SP score was an early lytic protein, K5. Treatment of BJAB K5-FLAG cells with ⍺Fas, an apoptotic stimulus, led to caspase-processing of full length K5-FLAG and generation of a C-terminal peptide fragment. Using mass spectrometry, we determined that K5-FLAG undergoes caspase cleavage at D222. K5 was also cleaved by caspases in KSHV infected cells induced to lytic replication. Importantly, the expression of K5-FLAG significantly inhibited ⍺Fas-induced caspase-mediated cell death. To determine if K5 plays a protective role in KSHV infected cells, iSLKK cells infected with wild type or K5 knockout BAC16 virus were induce to lytic replication to activate caspases. Although lytic induction showed little effect on the viability of WT infected cells, the viability of K5-knockout cells decreased by 25%. Thus, K5 may protect KSHV-infected cells from caspase-mediated cell death during lytic replication. Interestingly, cleavage of K5 by caspases did not affect its ability to downregulate MHC-1 surface expression. Overall, these data suggest that K5 not only downregulates immunologic surface marker expression to avoid immune recognition but may also play an additional role in mitigating caspase-mediated cell death during KSHV lytic replication.

DOI: https://doi.org/10.1101/2025.04.08.647834

Exp Mol Med. 2025 Jun 24.

Caspases as master regulators of programmed cell death: apoptosis, pyroptosis and beyond.

So Hee Dho, Minjeong Cho, Wonjin Woo, Seolhee Jeong, Lark Kyun Kim.

Caspases are crucial regulators of programmed cell death, mediating pathways such as apoptosis, pyroptosis, necroptosis and ferroptosis. Their activity is intricately controlled by epigenetic modifications, molecular interactions and post-translational changes, reflecting their central role in cellular homeostasis and disease mechanisms. Dysregulated caspase functions are linked to a wide array of conditions, including cancer, neurodegenerative disorders and inflammatory diseases, establishing their importance as potential therapeutic targets. The roles and regulation of caspases across subcellular compartments and their molecular interactions provide critical insights into the complexity of programmed cell death. Here, this review synthesizes current knowledge on the diverse functions of caspases, offering a comprehensive foundation for exploring innovative therapeutic strategies.

DOI: https://doi.org/10.1038/s12276-025-01470-9