bims-cediti 2026-09-27 papers

Issue of 2026–09–27
five papers selected by
Kateryna Shkarina, Universität Bonn

Cell Rep. 2026 Sep 22. pii: S2211-1247(26)01115-0. [Epub ahead of print]45(10): 118037

Processing of lysophosphatidylcholines by ExoU secreted by P. aeruginosa leads to inflammasome activation and cell death.

Pseudomonas aeruginosa (P. aeruginosa) thrives in the lungs of patients with cystic fibrosis (CF) which results in pulmonary inflammation and decline in lung function. Inflammasome signaling promotes host cell death and processing of IL-1 which results in bacterial control. Since the type 3 secretion system (T3SS) of P. aeruginosa induces inflammasome signaling, we evaluated the role of ExoU, a phospholipase which is secreted through the T3SS and promotes host susceptibility. Our results indicate that the genes associated with T3SS-function display increased polymorphism and are poorly expressed in the chronic isolates of P. aeruginosa from patients with CF, which leads to poor inflammasome activation. ExoU, secreted by P. aeruginosa modulates the lipidome of infected cells extensively, which results in an increase in the intracellular levels of lysophosphatidylcholine species that leads to the activation of NF-κB and MAPK pathways and cell death by inflammasome signaling, which is inhibited by lysophosphatidylcholine acyltransferase 3 (LPCAT3).

Keywords: CP: microbiology; Pseudomonas aeruginosa; cell death; cystic fibrosis; inflammasome signaling; inflammation; innate immune response; lipidome; macrophages; type 3 secretion system

DOI: https://doi.org/10.1016/j.celrep.2026.118037

Nat Commun. 2026 Aug 25. pii: 10178. [Epub ahead of print]17(1):

Exosomal export of activated CASPASE-8 is linked to the prevention of TNF-induced cytotoxicity.

Jon Huyghe, Dario Priem, Annelore Haems, Lien Lippens, Margaux De Meyer, Tom Delanghe, Yves Dondelinger, Inge Bruggeman, Peter Vandenabeele, Sven Eyckerman, An Hendrix, Mathieu Jm Bertrand.

Tumor Necrosis Factor (TNF) is a key pro-inflammatory cytokine whose sensing by TNFR1 triggers gene activation or cell death induction. While TNF cytotoxicity can be beneficial during infections by supporting effective immune responses, its chronic or excessive induction is harmful and promotes inflammatory pathologies. Protective brakes, known as cell death checkpoints, normally repress TNF cytotoxicity and therefore constitute crucial safeguards against these diseases. Death by TNF mainly proceeds upon inactivation of a checkpoint by microbial effector proteins or pathological mutations. We previously identified lysosomal turnover of TNFR1 Complex II by TAX1BP1-mediated selective macro-autophagy as a brake on TNF cytotoxicity. Here, we propose an alternative mechanism that prevents TNF-induced RIPK1 kinase-independent apoptosis. We found that inhibiting the ESCRT machinery, HSC70 or TAX1BP1 interferes with the TNF-dependent targeting of activated CASPASE-8 into endosomal intralumenal vesicles (ILVs) and is associated with apoptosis induction. Furthermore, we identified TAX1BP1 and TNFR1 Complex II components as TNF-induced cargoes of extracellular vesicles, suggesting that exosomal release of TNFR1 Complex II serves as a parallel detoxification pathway to lysosomal turnover. Finally, we show that Salmonella Typhimurium and Mycobacterium tuberculosis effector proteins activate TNF cytotoxicity by inhibiting components of the ESCRT machinery involved in this detoxification process.

DOI: https://doi.org/10.1038/s41467-026-75544-1

J Mol Biol. 2026 Sep 23. pii: S0022-2836(26)00403-1. [Epub ahead of print] 170030

Structural Insights into MLKL-Mediated Necroptosis: Emerging Mechanisms.

Brooke Dreyer, Jianbin Ruan.

Necroptosis is a regulated form of lytic cell death that plays important roles in inflammation, host defense, and disease. Central to this pathway is mixed lineage kinase domain-like protein (MLKL), the terminal effector responsible for membrane disruption. Upon phosphorylation by receptor-interacting protein kinase 3 (RIPK3), MLKL undergoes conformational changes, oligomerizes, and translocates to cellular membranes. Despite extensive study, however, the detailed molecular mechanism by which MLKL mediates necroptosis remains incompletely understood. Multiple models have been proposed, including pore formation, cation channel activity, and higher-order or amyloid-like assemblies, yet each is supported by limited and often indirect evidence. Notably, high-resolution structures of membrane-associated, active MLKL assemblies are still lacking, hindering a unified mechanistic understanding. In addition, emerging studies suggest that membrane permeabilization and terminal membrane rupture may be mechanistically distinct processes, potentially involving additional effectors such as SIGLEC12. In this review, we summarize current structural and mechanistic insights into MLKL, including its domain architecture, activation mechanisms, and species-specific divergence. We then evaluate competing models of MLKL-mediated membrane disruption and highlight key challenges and future directions. We emphasize the need to directly visualize the active, oligomeric MLKL assemblies in the membrane-bound state and to integrate structural, biochemical, and cellular approaches for a comprehensive understanding of MLKL-mediated membrane permeabilization. Resolving these questions will be essential for understanding necroptosis and for developing therapeutic strategies targeting MLKL-mediated cell death.

Keywords: MLKL; Necroptosis; RIPK1; RIPK3; SIGLEC12; membrane permeabilization; membrane rupture; pseudokinase

DOI: https://doi.org/10.1016/j.jmb.2026.170030

Cell. 2026 Sep 22. pii: S0092-8674(26)01022-6. [Epub ahead of print]

Switching of transcriptional control from interferon regulatory factor 2 to interferon regulatory factor 1 drives innate immune cell activation.

Interferon regulatory factor 2 (IRF2) is a transcription factor that prevents skin inflammation in mice and humans but, paradoxically, promotes pyroptosis by upregulating gasdermin D. How IRF2 activates some proinflammatory genes but suppresses inflammation is unclear. We show that skin inflammation in Irf2-deficient mice is driven by IRF1 activation of interferon-stimulated genes (ISGs). Chromatin profiling reveals that IRF1 and IRF2 occupy the same ISG regulatory sites, but as a weaker transcriptional activator, IRF2 limits ISG transcription by IRF1. Toll-like receptor (TLR) signaling favors IRF1-driven transcription by inducing Irf1. In addition, IRF1 recruits the ubiquitin ligase SPOP to ISG sites, resulting in proteasomal degradation of IRF2. This shift from IRF2 to IRF1 occupancy enhances ISG transcription. Collectively, these findings define a hierarchical transcriptional circuit in which IRF2 limits IRF1 activity under homeostatic conditions but is displaced during an immune response, allowing IRF1-dependent gene programs central to innate immunity and autoinflammation.

Keywords: IRF1; IRF2; ISGs; SPOP; Toll-like receptor

DOI: https://doi.org/10.1016/j.cell.2026.08.049

Sci Adv. 2026 Sep 25. 12(39): eaef2562

Airway epithelia clear rhinovirus infection via two waves of cell extrusion.

Faith Fore, Dustin C Bagley, Rocio Teresa Martinez-Nunez, Julia Aniscenko, Sebastian Johnston, Jody Rosenblatt.

Epithelial barriers represent the first line of defense against pathogens, yet their role in innate immunity is typically relegated to pathogen detection and immune cell recruitment. This perspective ignores a fundamental biological principle: Epithelia defended against pathogens long before complex immune systems evolved. Here, we demonstrate that human bronchial epithelium retains this ancestral capacity, autonomously clearing rhinovirus (RV) within 24 hours by selectively extruding infected cells, a process that we term virus-induced cell extrusion (VICE). VICE occurs in two waves: a rapid response occurring independently of complete virus entry, followed by a replication-dependent wave. Barrier-defective epithelia that cannot extrude do not eliminate RV. While VICE maintains barrier integrity and reduces local infection, it also expels virus-laden cells, which can infect fresh epithelia. Thus, VICE enables leukocyte-independent epithelial defense while inadvertently promoting viral spread, redefining epithelia as central to viral pathogenesis and host protection.

DOI: https://doi.org/10.1126/sciadv.aef2562