bims-cediti 2026-03-15 papers

bims-cediti

Biomed News

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

Issue of 2026–03–15
eleven papers selected by
Kateryna Shkarina, Universität Bonn

Unified phase separation drives DNA-induced inflammasome activation of the AIM2-like receptors.
Mechanoresilience of lysosomes conferred by TMEM63A.
The ASC-c isoform as a modulator of inflammasome activation: insights into molecular mechanisms and therapeutic applications.
Structural basis and regulation of GSDME pore formation.
ADAR1 regulates dsRNA formation in nuclear and mitochondrial transcripts through editing-dependent and -independent mechanisms.
CD8+ T cell loss induces autoinflammation in inborn errors of cell death.
Interferon Stimulatory DNA activates the DNA damage signaling through ATM and DNA-PK sensing.
Protocol for precision cutting and short-term culture of lymph node tissue slices for modeling of innate immune responses ex vivo.
Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.
Conservation of NLRP3 Inflammasome Pathway in Monotremes and Large-Scale Restructuring of the Caspase-1 Gene Cluster Region in Mammals.
Chromosomal instability shapes the tumor microenvironment of esophageal adenocarcinoma via a cGAS-chemokine-myeloid axis.

Cell Rep. 2026 Mar 10. pii: S2211-1247(26)00143-9. [Epub ahead of print]45(3): 117065

Unified phase separation drives DNA-induced inflammasome activation of the AIM2-like receptors.

Xiangyu Huang, Yufei Zhang, Zhenchao Zhao, Xin Li.

  AIM2-like receptors (ALRs) are critical for host defense by sensing intracellular foreign DNA and aberrant self-DNA to activate inflammasomes. Here, we demonstrate that both human and mouse AIM2 undergo liquid-liquid phase separation (LLPS) upon binding dsDNA. Multivalent interactions within the OB1 and OB2 subdomains of the AIM2 HIN domain are essential for LLPS and subsequent inflammasome activation. In AIM2 knockout THP-1 cells, LLPS-deficient AIM2 mutants exhibit markedly impaired inflammasome activation and antiviral responses. ASC recruitment promotes the solidification of AIM2-dsDNA condensates. Notably, HIN domains from multiple ALRs, including human AIM2, human IFI16, mouse AIM2, and porcine MNDAL, form dsDNA-induced condensates, suggesting that HIN-domain-mediated LLPS is a conserved mechanism across the HIN-200 family. Finally, we identify the α-herpesvirus tegument protein VP22 as a viral antagonist that disrupts AIM2-dsDNA LLPS to evade AIM2 inflammasome activation. Collectively, these findings elucidate a unified LLPS-dependent mechanism for ALR-mediated DNA sensing and inflammasome activation and uncover a viral immune evasion strategy targeting biomolecular condensates.

Keywords:  AIM2; ALRs; CP: immunology; CP: molecular biology; inflammasome; liquid-liquid phase separation; α-herpesvirus VP22

DOI:  https://doi.org/10.1016/j.celrep.2026.117065
J Cell Biol. 2026 May 04. pii: e202509180. [Epub ahead of print]225(5):

Mechanoresilience of lysosomes conferred by TMEM63A.

Angelina S Kim, Jing Ze Wu, Ruiqi Cai, Spencer A Freeman.

Lysosomes are subject to perturbations that can cause damage to their limiting membrane. Osmotic shifts, pore-forming toxins, and the growth of luminal polymers or pathogens all stand to increase lysosomal membrane tension and/or disrupt the bilayer. In some contexts, this leads to lysosomal rupture and cell death. Here, we describe a mechanism that enables lysosomes to sense and respond to acute increases in tension of their limiting membrane. We report that the lysosome-resident nonselective cation channel, TMEM63A, can drive the directional flux of monovalent cations, major osmoticants, out of the lumen when gated by mechanical tension on the organelle. This results in the ability for lysosomes to relieve hydrostatic pressure and, proportionally, membrane tension, affording lysosomes the time to acquire additional lipids. Lysosomes without this mechanism-either because TMEM63A is deleted or in the case when cells express disease-causing variants of TMEM63A-are an order of magnitude more sensitive to lysis upon increases to their membrane tension when compared with their WT counterparts. These findings suggest that lysosomes are capable of regulating hydrostatic pressure and volume in response to high tension.

DOI: https://doi.org/10.1083/jcb.202509180
J Biol Chem. 2026 Mar 06. pii: S0021-9258(26)00223-1. [Epub ahead of print] 111353

The ASC-c isoform as a modulator of inflammasome activation: insights into molecular mechanisms and therapeutic applications.

Meenakshi Sharma, Anthony Waterston, Christopher J Randolph, Lauren E Stark, David M Gravano, Michael E Colvin, Eva de Alba.

Canonical inflammasome assembly is driven by interactions between sensors and effector procaspase-1, primarily mediated by the adaptor ASC. Homotypic interactions between Death Domains pyrin (PYD) and caspase recruitment and activation domain (CARD) lead to sensor and ASC oligomerization, along with the recruitment of procaspase-1. ASC self-association is essential for inflammasome activation, which initiates inflammatory responses. Therefore, uncontrolled inflammasome activation contributes to chronic inflammatory diseases. ASC-c, an isoform of ASC, acts as a negative regulator of the inflammasome. To better understand ASC-c's regulatory role, we examined its structural properties and interactions with ASC. Our nuclear magnetic resonance data show that ASC-c's CARD is properly folded, whereas the PYD consists of two α-helices instead of the six-helix bundle typical of Death Domains. In addition, a chemical shift perturbation analysis indicates that ASC-c interacts with ASC. We obtained transmission electron micrographs revealing that ASC-c polymerizes into filaments and filament bundles, which display greater heterogeneity than those of ASC based on dynamic light scattering. Overall, our results suggest that ASC-c binding to ASC can have an impact on ASC self-association, thereby affecting inflammasome assembly. Based on these findings, we designed a peptide encompassing the two helices of the ASC-c PYD to target ASC for therapeutic purposes. We demonstrate the interaction between the peptide and ASC by fluorescence anisotropy and show the stability of the complex by molecular dynamics simulations. Finally, cell-based assays measuring inflammasome activation indicate an inhibitory effect of the ASC-c peptide, pointing to its potential use in drug design.

DOI: https://doi.org/10.1016/j.jbc.2026.111353
Nat Commun. 2026 Mar 13.

Structural basis and regulation of GSDME pore formation.

Evelyn Teran, Tian Tian, Chengliang Wang, Xinzheng Wang, Jinghan Wang, Dongchun Ni, Vijay A Rathinam, Jianbin Ruan.

Gasdermins (GSDMs) are pore-forming proteins that mediate pyroptosis and contribute to inflammatory and cancer-related processes. Although GSDME shares structural similarity with other gasdermins, its activation and pore assembly mechanisms remain incompletely defined. Here we determine high-resolution cryo-electron microscopy structures of 27- and 28-fold human GSDME pores at 3.64 Å and 3.58 Å resolution. The structures reveal conserved structural architecture together with distinct features, including an extended transmembrane β-barrel and a comparatively compact membrane-engagement geometry. Structure-guided mutagenesis identifies lipid-binding and oligomerization interfaces required for pore formation. We further demonstrate that caspase-3 activates GSDME through direct recognition of a DMPD tetrapeptide motif within the interdomain linker, independently of the GSDME C-terminal domain. Following proteolytic activation, S-palmitoylation of GSDME N-terminal domain enhances pore-forming efficiency, with Cys180 serving as the primary functional site. Together, these findings establish a coordinated structural and regulatory framework in which proteolytic licensing and lipid modification sequentially control GSDME pore formation.

DOI: https://doi.org/10.1038/s41467-026-70643-5
Cell Rep. 2026 Mar 06. pii: S2211-1247(26)00104-X. [Epub ahead of print]45(3): 117026

ADAR1 regulates dsRNA formation in nuclear and mitochondrial transcripts through editing-dependent and -independent mechanisms.

Heegwon Shin, Tyler J Dorrity, Justin Aruda, Kenenni A Wiegand, Jung Seung Nam, Jiping Yang, Aidan S Jones, Jake A Gertie, Meera K Singh, Yuanjun Yin, Keer He, Rafan Sarker, Rajesh K Soni, Yousin Suh, Iok In Christine Chio, Silvi Rouskin, Hachung Chung.

  Endogenous (self) double-stranded RNAs (dsRNAs) in human cells can activate innate immune responses. ADAR1, an A-to-I editing enzyme of dsRNAs, suppresses aberrant immune activation by self-dsRNAs. However, how ADAR1 influences the cellular dsRNA landscape remains unclear. We show that human ADAR1 downregulates self-dsRNA abundance through editing-dependent and editing-independent mechanisms. We further conducted quantitative dsRNA sequencing on wild-type and ADAR1-deficient cells. dsRNAs are enriched in protein-coding mRNAs-especially those with repetitive elements and elongated 3' UTRs-and mitochondrial RNAs. ADAR1-regulated dsRNA transcripts consist of nuclear-encoded mRNAs and, unexpectedly, mitochondria-encoded RNAs rarely edited by ADAR1. Accordingly, dsRNAs accumulate to high levels within the mitochondria of ADAR1-deficient cells. Mass spectrometry and biochemical assays can detect ADAR1p150 in mitochondrial fractions. Notably, ADAR1 loss sensitizes cells to inflammation under mitochondrial stress (e.g., herniation and X-ray irradiation). Hence, we show that dsRNAs regulated by ADAR1 go beyond A-to-I edited transcripts and that ADAR1 can control mitochondrial dsRNAs.

Keywords:  A-to-I editing; ADAR1; AGS; Aicardi-Goutieres syndrome; CP: immunology; CP: molecular biology; IFN; PKR; double-stranded RNA; dsRNA; dsRNA-seq; innate immunity; mitochondria; mitochondrial stress; protein kinase R; type 1 interferon

DOI:  https://doi.org/10.1016/j.celrep.2026.117026
Nat Commun. 2026 Mar 11.

CD8+ T cell loss induces autoinflammation in inborn errors of cell death.

Jialin Dai, Taijie Jin, Gaixiu Su, Xu Han, Jun Wang, Chenlu Liu, Wenjie Zheng, Qiuye Zhang, Ranran Zhang, Hye Sun Kuehn, Jun Yang, Li Guo, Dan Zhang, Ming Li, Yingjie Xu, Tong Yue, Min Wen, Jia Zhu, Min Kang, Jianming Lai, Feifei Wu, Shihao Wang, Jiahui Zhang, Ivona Aksentijevich, Sergio D Rosenzweig, Pui Y Lee, Junying Yuan, Xiaomin Yu, Qing Zhou.

Systemic autoinflammatory diseases (SAID) with inborn errors of cell death (IECD) are caused by overactivation of programmed cell death (PCD). However, the pathogenesis by which PCD leads to autoinflammation remains unclear. Here, we identified IECD patients carrying compound heterozygous RIPK1 variants K377E/R390G with autoinflammatory manifestations. Mechanistically, K377E and R390G mutations suppress NF-κB signaling and activate RIPK1 to promote cell death. CD8+ T cells of the patients displayed overactivated RIPK1 and excessive cell death, leading to an elevated CD4/CD8 ratio, which could also be detected in patients with cleavage-resistant mutation of RIPK1 or SHARPIN deficiency. We show that the increased cell death of CD8+ T cells promotes TNF and IFN-γ secretion to activate monocytes/macrophages, which triggers overproduction of proinflammatory cytokines. In addition, disruption of the communication between T cells and monocytes/macrophages through pharmacologic blockade of TNF and IFN attenuates proinflammatory cytokine production in macrophages and relieves all the symptoms in patients. This study further clarifies the mechanism for a group of IECD with SAID. Increased CD4/CD8 ratio and augmented RIPK1 activation in T cells provide potentially additional criteria for diagnosis of RIPK1-dependent IECD and a combination of TNF/JAK inhibitor could be an effective therapy for the diagnosed patients.

DOI: https://doi.org/10.1038/s41467-026-70317-2
J Biol Chem. 2026 Mar 09. pii: S0021-9258(26)00232-2. [Epub ahead of print] 111362

Interferon Stimulatory DNA activates the DNA damage signaling through ATM and DNA-PK sensing.

Samira Kemiha, Lorena Rejón-Franco, Estelle Ghibaudo, Roger J Eloiflin, Morgane Chemarin, Karim Hawillo, Nadine Laguette, Hervé Técher.

  In eukaryotic cells, DNA is normally confined in the nucleus and mitochondria and the presence of DNA in the cytoplasm is a danger signal that activates innate immune responses. Upon detection of cytoplasmic dsDNA in mammalian cells, the cGAS-STING pathway induces type I-Interferon (IFN-I) and inflammatory responses, a key step in innate immune activation. Since its discovery, Interferon Stimulatory DNA (ISD), a linear double-stranded DNA, has been largely used to study the cGAS-STING pathway and its regulation. Here, we show that ISD also stimulates DNA damage signaling. We show that ISD activates both ATM and DNA-PK, the sensor kinases of the DNA damage response, independently of cGAS-STING signaling. Our results demonstrate that the DNA damage response, which is usually considered a response to genomic DNA lesions, can be promoted by foreign DNA. Our data further suggest that ISDs coordinate two central protective functions of cells, the innate immunity and DNA damage checkpoints.

Keywords:  ATM; DNA damage response; DNA-PK; Interferon Stimulatory DNA; cGAS-STING pathway

DOI:  https://doi.org/10.1016/j.jbc.2026.111362
STAR Protoc. 2026 Mar 10. pii: S2666-1667(26)00074-2. [Epub ahead of print]7(1): 104421

Protocol for precision cutting and short-term culture of lymph node tissue slices for modeling of innate immune responses ex vivo.

Joannah R Fergusson, Mark Coles, Calliope A Dendrou, Anita Milicic.

  Secondary lymphoid organs are highly organized for the initiation of immune responses. Here, we present a protocol that enables this microanatomical structure to be preserved during short-term culture, allowing ex vivo modeling of human innate immune responses. We describe the steps for precision cutting of human lymph nodes into live tissue cross-sections that can be cultured for up to 20 h with immune stimuli and analyzed by multiple readouts. For complete details on the use and execution of this protocol, please refer to Fergusson et al.1.

Keywords:  cell culture; cell-based assays; immunology

DOI:  https://doi.org/10.1016/j.xpro.2026.104421
Nat Struct Mol Biol. 2026 Mar 13.

Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.

Kirandeep K Deol, Cynthia A Harris, Sydney J Tomlinson, Colin J Delaney, Amr Al-Farhan, Alyssa J Mathiowetz, Cody E Doubravsky, Derek A Pratt, James A Olzmann.

Ferroptosis, a regulated form of cell death driven by excessive lipid peroxidation, has emerged as a promising therapeutic target in cancer. Ferroptosis suppressor protein 1 (FSP1) is a critical regulator of ferroptosis resistance, yet the mechanisms controlling its expression and stability remain mostly unexplored. To uncover regulators of FSP1 abundance, we conducted CRISPR-Cas9 screens using a genome-edited, dual-fluorescent FSP1 reporter cell line, identifying both transcriptional and post-translational mechanisms that determine FSP1 levels. Notably, we identified riboflavin kinase and flavin adenine dinucleotide (FAD) synthase, enzymes that are essential for synthesizing FAD from vitamin B2, as key contributors to FSP1 stability. Biochemical and cellular analyses revealed that FAD binding is critical for both FSP1 activity and stability. FAD deficiency and mutations blocking FSP1-FAD binding triggered FSP1 degradation through a ubiquitin-proteasome pathway involving the E3 ligase RNF8. Unlike other vitamins that inhibit ferroptosis by scavenging radicals, vitamin B2 supports ferroptosis resistance through FAD cofactor binding, ensuring proper FSP1 stability and function. This study provides a rich resource detailing mechanisms that regulate FSP1 abundance and highlights a novel connection between vitamin B2 metabolism and ferroptosis resistance, with implications for therapeutic strategies targeting FSP1 in cancer.

DOI: https://doi.org/10.1038/s41594-026-01759-x
J Mol Evol. 2026 Mar 12.

Conservation of NLRP3 Inflammasome Pathway in Monotremes and Large-Scale Restructuring of the Caspase-1 Gene Cluster Region in Mammals.

David Stevens, Tasman Daish, Frank Grützner.

  Activation of the NLRP3 inflammasome can be triggered by components of fungi, bacteria and viruses, as well as cellular stress and environmental irritants. The NLRP3 inflammasome has been well characterised in mouse and humans but limited information is available from other mammalian species. To gain a better understanding of the evolution of genes involved in the NLRP3 inflammasome pathway, we examined them in mammalian species representing the three major lineages (eutheria, metatheria and prototheria) and in chicken as an outgroup. Our results show that the inflammasome pathway machinery is generally well conserved in the species examined. We identified four NLRP members in echidna and seven in platypus as well as confirming Nlrp3 is present in marsupials and monotremes. Monotremes feature eleven Dectin family genes that are split across two chromosomes. Only three family members were found in opossum, Tasmanian devil and koala. Of the four Dectin family members known to be involved in the NLRP3 inflammasome pathway only Clec4e (Mincle) was identified in all species examined. Echidna possesses a single copy of Caspase-1 which, alongside previous results reported in the platypus, supports the conclusion that this is the only proinflammatory caspase in the monotremes. Our analysis suggests that Caspase-1 moved to a new chromosomal region in early mammalian evolution. This was followed by expansion of the cluster and accumulation of additional genes. The expansion of key gene families flanking Caspase-1 may have led to an expansion of inflammasome pathways and a more regulated immune system through the CARD genes.

Keywords:  Comparative Immunology/Evolution; Gene Rearrangement; Inflammasome; Inflammation; Mammalian gene evolution; Phylogenetics

DOI:  https://doi.org/10.1007/s00239-026-10307-6
Sci Adv. 2026 Mar 13. 12(11): eaeb1611

Chromosomal instability shapes the tumor microenvironment of esophageal adenocarcinoma via a cGAS-chemokine-myeloid axis.

Bruno Beernaert, Rose L Jady-Clark, Parin Shah, Erik Ramon-Gil, Nora M Lawson, Zack D Brodtman, Somnath Tagore, Frederik Stihler, Alfie S Carter, Shannique Clarke, Tong Liu, Winston M Zhu, Juliet E Martin, Erkin Erdal, Alistair Easton, Leticia Campo, Molly Browne, Stephen Ash, Rabial Q Raja, Nicola Waddell, Tom Crosby, Simon R Lord, Derek A Mann, Ignacio Melero, Carlos E de Andrea, Andréa E Tijhuis, Floris Foijer, Ester M Hammond, Kadir C Akdemir, Jack Leslie, Benjamin Izar, Eileen E Parkes.

Chromosomal instability (CIN), a pervasive feature of esophageal adenocarcinoma (EAC), drives tumor aggressiveness and metastasis. CIN stimulates the cGAS-STING pathway, typically linked to antitumor immunity. However, despite the high CIN burden in EAC, the cGAS-STING pathway remains largely intact. To address this paradox, we interrogated multiple esophageal cancer models, finding myeloid-attracting chemokines-with CXCL8 as a prominent hit-as conserved CIN-driven targets in EAC. Using multiplexed immunofluorescence microscopy, we quantified ongoing CIN in human EAC tumors by measuring cGAS-positive micronuclei, validated by whole-genome sequencing. Coupling in situ CIN detection with single-nucleus RNA sequencing and multiplex immunophenotyping of human EAC, we link CIN to tumor-intrinsic innate immune activation, CXCL8 expression, and myeloid cell-mediated immunosuppression. In patients with EAC, CINhigh, myeloid-dominated tumors correlate with poor outcomes and aberrant cGAS-STING signaling. These insights explain the counterintuitive maintenance of cGAS-STING and highlight the disruption of the CIN-cGAS-inflammation axis as a potential therapeutic strategy in EAC.

DOI: https://doi.org/10.1126/sciadv.aeb1611