bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–08–16
seven papers selected by
Kateryna Shkarina, Universität Bonn
  1. Sorcin couples Annexin A11 recruitment to ESCRT-III assembly for plasma membrane repair.
  2. Mechanism and plasticity of primitive pyroptosis.
  3. Structural and molecular principles of DAMP biology.
  4. PKR engages viral RNA and intron-retained host transcripts during poxvirus infection.
  5. Regulation of inflammation by oxidized lipids.
  6. Loss of cellular RNA homeostasis contributes to MDA5 activation during virus infection.
  7. Chromatin condensates tune nuclear mechanosensing and preserve nuclear integrity to prevent cGAS activation.
  1. Proc Natl Acad Sci U S A. 2026 08 18. 123(33): e2610420123
    Sorcin couples Annexin A11 recruitment to ESCRT-III assembly for plasma membrane repair.
    Jordan Matthew Ngo, Justin Krish Williams, Abinayaa Murugupandiyan, Randy Schekman.
      The absence of a cell wall affords animal cells diverse functionality at the cost of acute sensitization to plasma membrane (PM) damage. Thus, animal cells tightly monitor and maintain PM integrity to prevent cell death. Genetic loss of PM repair factors is associated with human diseases such as muscular dystrophy. Despite evidence that annexin and endosomal sorting complex required for transport (ESCRT) proteins are required for PM repair, the extent to which their recruitment is coordinated at sites of membrane damage remains unclear. Here, leveraging quantitative organellar proteomics and genome-wide CRISPR interference screens, we identify sorcin as a PM repair factor that couples annexin A11 (ANXA11)-mediated sensing of PM damage to ESCRT-III assembly. We show that sorcin directly binds ANXA11 and ALIX in the presence of Ca2+ via its penta-EF-hand domain and flexible N terminus, respectively, and is required for ESCRT-III recruitment to PM lesions and membrane resealing. Our data support a model in which ANXA11, recruited to the PM upon damage-induced Ca2+ influx, serves as an anchor that facilitates the sequential recruitment of sorcin and ESCRT-III at PM lesions. Together, these findings establish a Ca2+-dependent scaffolding mechanism that couples PM damage sensing to ESCRT-III assembly for PM repair.
    Keywords:  annexin; endosomal sorting complex required for transport (ESCRT); membrane repair; plasma membrane
    DOI:  https://doi.org/10.1073/pnas.2610420123
  2. Sci Adv. 2026 Aug 14. 12(33): eaed2720
    Mechanism and plasticity of primitive pyroptosis.
    Zhi Su, Man Huang, Jianhua Gan, Zhaoxiang He, Yuanyuan Wang, Yuanwei Zhang, Jiuxin Qu, Long Zhou, Changbin Chen, Yu Feng, Zheng-Guo He, Youjun Feng.
      Pyroptosis is a proinflammatory form of regulated cell death across the tree of life. The gasdermin (GSDM) protein family functions as an evolutionarily conserved executioner of pyroptotic cell death by forming membrane pores. As the canonical activation mechanism, proteolytic cleavage drives the formation of GSDM pores. In contrast to the well-studied modern GSDM-directed pyroptotic pathway, biochemical mechanisms of primitive GSDM pores are poorly understood. Here, we functionally characterize two primitive GSDM variants with cytotoxicity, one of which is a bacterial homolog (termed bGSDM) from Runella zeae, and the other refers to a fungal homolog (fGSDM/HET-Q1) of Podospora anserina. The cleavage of bGSDM (or fGSDM/HET-Q1) by two distantly related proteases enables the in vitro reconstitution of GSDM progenitor-gated pyroptotic pores on liposome. In particular, we present high-resolution cryo-electron microscopy structures of two primitive pyroptotic pores, consisting of a Runella bGSDM ring at 3.25 angstroms and a Podospora fGSDM pore at 2.68 angstroms. Unlike the large bGSDM pore arranged in 46-fold symmetry, the smallest fGSDM pore is composed of 20 HET-Q1 protomers. Structure-to-function studies illuminate how bGSDM/fGSDM protomers assemble into distinct membrane pores. We also investigate the feasibility of engineering primitive GSDM pores to counter top-priority bacterial/fungal pathogens. Collectively, our findings offer a primitive mechanism for lytic cell death executed by flexible pores.
    DOI:  https://doi.org/10.1126/sciadv.aed2720
  3. Nat Struct Mol Biol. 2026 Aug;33(8): 1131-1146
    Structural and molecular principles of DAMP biology.
    Ruochan Chen, Ju Zou, Jie Li, Jiawang Chen, Xiao Zhong, Jiao Liu, Rui Kang, Huiting Zhou, Daolin Tang.
      Damage-associated molecular patterns (DAMPs) are endogenous danger signals. They can be preformed molecules released upon membrane rupture and stress-induced or newly generated factors arising during cell death. These signals link cellular demise to diverse host responses. Rather than passive by-products, DAMPs are actively mobilized through membrane-remodeling proteins, vesicular trafficking and metabolic regulation. Conformational changes, oligomerization and post-translational modifications shape their release and immunogenicity, as illustrated by redox-dependent DAMP states, pore-forming gasdermins and MLKL, and NINJ1-mediated membrane rupture. At the sensing interface, receptors such as TLR4, P2X7 and AGER, together with cytosolic STING1 pathways, translate DAMP recognition into downstream signaling through assembly-driven mechanisms. Cross-talk with metabolic pathways and membrane repair systems, including ESCRT-III and autophagy, further refines DAMP signaling dynamics. Here, we survey and contextualize recent literature to provide a structural and molecular framework for understanding how DAMPs encode immune outcomes and highlight opportunities for targeted therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41594-026-01858-9
  4. Cell Rep. 2026 Aug 08. pii: S2211-1247(26)00916-2. [Epub ahead of print]45(8): 117838
    PKR engages viral RNA and intron-retained host transcripts during poxvirus infection.
    Ruilin Zhang, Xiang Ye, Andrew C Dixson, Yang Zhao, Alissa M Weaver, John Karijolich.
      Recognition of double-stranded (ds) RNA is central to antiviral defense, yet how RNA sensors are activated during infection remains unclear. Here, we demonstrate that during vaccinia virus (VacV) infection, PKR binding is enriched on viral RNAs and host-intron-containing transcripts. During infection, RNase L activation impaired pre-mRNA splicing, promoting accumulation of cytoplasmic intron-retaining transcripts. Small-molecule inhibition of splicing activated PKR independently of RNase L, supporting defective pre-mRNA splicing as a source of PKR ligands. PKR also engaged structured viral RNAs, including telomere-derived species with distinct activating properties. PKR signaling was further shaped by the cellular RNA-binding protein PACT, which enforces a dsRNA abundance threshold for activation, and suppressed by the viral antagonist E3. These findings reveal that PKR monitors both virus-derived and processing-defective host RNAs during infection, establishing cooperativity at the intersection of RNA processing, viral replication, and innate defense.
    Keywords:  CP: immunology; CP: molecular biology; OAS; PKR; RNase L; antiviral immunity; dsRNA; poxvirus; vaccinia virus
    DOI:  https://doi.org/10.1016/j.celrep.2026.117838
  5. Sci Immunol. 2026 Aug 14. 11(122): eadv9397
    Regulation of inflammation by oxidized lipids.
    Marco Di Gioia, Ivan Zanoni.
      Host-derived lipids undergoing enzymatic or nonenzymatic oxidation play critical roles in regulating inflammation. Polyunsaturated fatty acids, cholesterol, and cholesterol intermediates can be enzymatically oxidized and serve as signaling mediators controlling tissue homeostasis and immunity. Spontaneously generated oxidized lipids, including nonenzymatically oxidized phospholipids (oxPLs), result from oxidative stress and accumulate during inflammation, affecting cellular metabolism, immune cell functions, and cell fate. These distinct classes of oxidized lipids not only share overlapping inflammatory roles but also exhibit divergent effects depending on their molecular structures and cellular targets. This Review highlights the double-edged nature of oxPLs: Although their transient production triggers protective responses, their accumulation sustains inflammation, contributing to tissue damage. We also discuss the emerging roles of oxPLs in cell death programs, immune cell activation, and stromal cell functions, which are critical processes favoring tumor growth. Overall, we highlight how oxidized lipids orchestrate immune responses and explore their contribution to infectious diseases and cancer.
    DOI:  https://doi.org/10.1126/sciimmunol.adv9397
  6. Nat Immunol. 2026 Aug 11.
    Loss of cellular RNA homeostasis contributes to MDA5 activation during virus infection.
    Natália G Sampaio, Tanja Davis, Linden J Gearing, Antonio G Dias Junior, Lise Chauveau, Georgie Wray-McCann, Valerie Odon, Vladyslava Liudkovska, Alexandra L McAllan, Chiara Cursi, Alice Mayer, Madara Ratnadiwakara, Minna-Liisa Änkö, Maciej Cieśla, Paul J Hertzog, Jan Rehwinkel.
      MDA5 is an innate immune RNA sensor that senses infection with a range of viruses and other pathogens. MDA5's RNA agonists are not well defined. Here we used single-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) to study its ligands. Of note, upon infection with SARS-CoV-2 or encephalomyocarditis virus, MDA5 bound overwhelmingly to cellular RNAs. Many binding sites were intronic and proximal to Alu elements and to potentially base-paired structures. Concomitantly, cytoplasmic levels of aberrant transcripts and intron-containing unspliced transcripts increased in infected cells and displayed enrichment of MDA5 iCLIP peaks. Moreover, overexpression of the splicing factor SRSF3 reduced aberrant transcription and abrogated MDA5 activation. Taken together, we propose that MDA5 surveys RNA processing fidelity and can detect infections by sensing perturbations of post-transcriptional events such as splicing.
    DOI:  https://doi.org/10.1038/s41590-026-02614-3
  7. EMBO J. 2026 Aug 12.
    Chromatin condensates tune nuclear mechanosensing and preserve nuclear integrity to prevent cGAS activation.
    Sarah D'Annunzio, Martina Di Santo, Giulia Vitali, Lucia Santomaso, Daniela Michelatti, Leonardo Morelli, Chiara Bernardis, Maulana Ariefai, Shiza Nasir, Sara Lago, Lorenzo Lunelli, Claudia Testi, Emanuele Pontecorvo, Alessandro Poli, Fabrizio A Pennacchio, Paolo Maiuri, Elodie Sanchez, David Genevieve, Lorenzo Petrolli, Thomas Tarenzi, Roberto Menichetti, Raffaello Potestio, Giancarlo Ruocco, Alessio Zippo.
      Cells and tissue integrity are constantly challenged by the necessity to adapt and respond to mechanical loads. Among cellular components, the nucleus possesses mechano-sensing and mechanotransduction capabilities, yet the molecular mechanisms involved remain poorly defined. Here we investigate whether the mechanical properties of chromatin and its organization into condensates contribute to nuclear adaptation to external forces, while preserving its integrity. By interrogating the effects of MLL4 loss-of-function in Kabuki Syndrome, we find that the balancing of transcriptional and Polycomb condensates tunes nuclear responsiveness to external mechanical forces. MLL4 assembles into mechanosensitive condensates through its prion-like domain, and this response is regulated by the chromatin context. Furthermore, the mechano-sensing activity of MLL4 condensates is instrumental to withstand the physical challenges nuclei experience during cell confinement and migration by preserving their integrity. In Kabuki Syndrome, persistent nuclear envelope rupture triggers cGAS-STING activation, leading to programmed cell death. Together, these findings identify chromatin condensates as active regulators of nuclear mechanosensing and establish a mechanistic link between defective chromatin organization and cGAS-STING activation in Kabuki syndrome.
    DOI:  https://doi.org/10.1038/s44318-026-00884-z
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