bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–10–11
sixteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. Canonical Wnt induction by OTULIN prevents keratinocyte death and skin inflammation.
  2. Exercise promotes host anti-infection activity through CNDP2 metabolite-mediated inflammasome hyperactivation.
  3. L-Arginine inhibits NLRP3 inflammasome activation.
  4. Infection of macrophages by mpox virus activates inflammasome and cell death, informing multitarget therapeutic strategies.
  5. Death domain-mediated higher-order oligomerization of RIPK1 drives TNF-induced signaling.
  6. Establishing the molecular basis for MDA5 mutation-linked autoimmunity.
  7. Macrophages discriminate and sort pathogenic bacteria and apoptotic material during dual-target phagocytosis.
  8. GAPDH nuclear signaling regulates neutrophil migration and inflammatory skin responses.
  9. Early recruitment of membrane-bound DNaseX to phagocytic cups in macrophages.
  10. Structural and Mechanistic Insights Into GSDME Pore Formation and Functional Regulation.
  11. Diverse infections transcriptionally reprogram the intestinal epithelium and epithelial-immune cell interactions.
  12. A non-canonical function of glutathione to suppress ferroptosis via FSP1.
  13. Deoxysphingolipids activate cGAS-STING and enhance antitumor immunity.
  14. 5-oxoETE links redox control of epithelial damage detection and resilience.
  15. DNASE1L3 maintains homeostatic levels of mitochondrial DNA on the mammalian cell surface.
  16. MATRIN3 deficiency in human cells triggers an autoinflammatory response via cGAS-STING activation.
  1. Sci Adv. 2026 Oct 09. 12(41): eadz0181
    Canonical Wnt induction by OTULIN prevents keratinocyte death and skin inflammation.
    Kim Lecomte, Pieter Hertens, Virginie Wylleman, Annagiada Toniolo, Febe Roelandt, Fleur Boone, Maarten Ciers, Lien Verboom, Katrien Staes, Geert van Loo, Esther Hoste.
      Loss-of-function mutations in the human OTULIN gene, encoding a deubiquitinase with exclusive specificity for linear ubiquitin chains, cause a severe multiorgan autoinflammatory condition involving the skin. Mice lacking OTULIN selectively in keratinocytes develop inflamed skin lesions that progress into squamous tumors, a phenotype driven by excessive tumor necrosis factor (TNF)-induced cell death. Previous studies suggest a role for OTULIN in mediating Wnt signaling during development, but the physiological relevance of this association is unknown. Here, we show that OTULIN promotes Wnt signaling in keratinocytes by regulating the linear ubiquitination status of β-catenin. Stabilization of β-catenin in OTULIN-deficient keratinocytes prevents progressive skin inflammation in prophylactic and therapeutic settings by blocking keratinocyte death. We demonstrate that OTULIN prevents proteasomal degradation of β-catenin in cultured keratinocytes. Reduced Wnt signaling in OTULIN-deficient keratinocytes leads to degradation of TCF3/4, an essential survival factor for keratinocytes. Collectively, our data identify OTULIN's linear deubiquitination activity as a key regulator of epithelial cell viability, not only by preventing cell death downstream of TNF, but also by promoting canonical Wnt signaling.
    DOI:  https://doi.org/10.1126/sciadv.adz0181
  2. PLoS Pathog. 2026 Oct;22(10): e1014554
    Exercise promotes host anti-infection activity through CNDP2 metabolite-mediated inflammasome hyperactivation.
    Yan Qian, Xiangyun Cheng, Qiannv Liu, Chunlei Wang, Chun Kong, Mengqian Li, Xiangyang Geng, Liya Ai, Mindi Zhao, Shuo Wang, Dong Jiang, Pengyan Xia.
      Exercise can enhance the body's ability to resist infections, but its molecular mechanisms are still unclear. Here, we found that exercise can induce a hyperactivation-like state of the NLRP3 inflammasome during infection, which enhances the body's ability to resist infection by continuously secreting inflammatory cytokines and reducing immune cell pyroptosis. At the molecular level, exercise enhances the binding between CNDP2 and GSDMD, promoting the production of γ-Glu-Cys. γ-Glu-Cys binds to CypD and inhibits the binding between CypD and GSDMD, thereby avoiding further damage to the mitochondrial inner membrane during the occurrence of inflammasomes. Limited mitochondrial DNA leakage allows the NLRP3 inflammasome to a hyperactivate state. Our findings reveal the molecular mechanisms by which exercise enhances the body's ability to resist infections, and provide possible standards for better guiding exercise intensity to improve anti-infection capabilities in the future.
    DOI:  https://doi.org/10.1371/journal.ppat.1014554
  3. Nat Metab. 2026 Oct 06.
    L-Arginine inhibits NLRP3 inflammasome activation.
    Feng Liu, Wanxin Zhuang, Yuan Yang, Wenting Zhao, Chao Zhang, Siyuan Li, Xudong Liu, Qingyuan Cao, Shunguo Zhu, Bingyu Liu, Xiangyu Ma, Lintai Da, Chengjiang Gao.
      Nutritional status and metabolic homeostasis are intricately associated with the inflammatory response. However, the direct mechanistic link between nutrition, metabolism and inflammation remains unclear. Here, we show that the amino acid L-arginine (L-Arg) is a potent endogenous inhibitor of the NLRP3 inflammasome, a central component of the inflammatory signalling pathway. We show that L-Arg binds directly to the Asp31 site of the NLRP3 protein, blocking its interaction with the adaptor ASC and subsequent inflammasome assembly and activation. L-Arg supplementation inhibits the NLRP3 inflammasome activation in macrophages, while deprivation promotes it. Treatment with L-Arg in mice alleviates monosodium urate crystal-induced arthritis and aluminium-induced peritonitis. In addition, L-Arg supplementation alleviates neuroinflammation and motor deficits in mouse models of Parkinson's disease, whereas L-Arg deprivation exacerbates pathology. In patients with Parkinson's disease, L-Arg levels are reduced in serum. Our study establishes L-Arg supplementation as a promising therapeutic avenue for managing NLRP3-driven inflammatory pathologies.
    DOI:  https://doi.org/10.1038/s42255-026-01636-3
  4. Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2623018123
    Infection of macrophages by mpox virus activates inflammasome and cell death, informing multitarget therapeutic strategies.
    Yining Wang, Xin Wang, Theano Tsikari, Fang Qin, Fangfang Chang, Fuxiang Wang, Ana Maria Gonçalves da Silva, Rick Schraauwen, Dewy Mae Offermans, Yijin Wang, Harry L A Janssen, Pengfei Li, Wenshi Wang, Valeria V Orlova, Amaro Nunes Duarte-Neto, Yang Yang, Qiuwei Pan.
      Severe mpox virus (MPXV) infection causes immunopathological manifestations in patients. Here, we provide clinical evidence of MPXV-induced inflammation in a large patient cohort and demonstrate direct macrophage infection in skin tissues from an autopsied mpox patient. In human macrophages, MPXV efficiently enters, replicates, and produces infectious particles. Infection activates both AIM2 and NLRP3 inflammasomes, triggering inflammatory responses and three forms of programmed cell death: pyroptosis, apoptosis, and necroptosis. Inflammasome inhibition reduces MPXV-induced inflammation and cell death without affecting viral replication. Screening clinically used anti-inflammatory drugs identified flufenamic acid, which suppresses MPXV-induced inflammation and cell death and, unexpectedly, also inhibits viral infection. Combined treatment with flufenamic acid and the antiviral brincidofovir further enhances suppression of viral infection, inflammatory response, and cell death, while largely preventing MPXV-induced transcriptomic reprogramming in macrophages. These effects were consistent across clade IIb, Ia, and Ib strains associated with the 2022-2023 global and recent African outbreaks. Together, our findings provide insight into MPXV immunopathology and support multitarget therapeutic strategies for severe mpox.
    DOI:  https://doi.org/10.1073/pnas.2623018123
  5. Cell Death Differ. 2026 Oct 08.
    Death domain-mediated higher-order oligomerization of RIPK1 drives TNF-induced signaling.
    Ying Chen, Jianwei Li, Yaw Bia Tan, Lihua Lai, Ping Liu, Ita Novita Sari, Anandhkumar Raju, Vinh Thang Huynh, Amhed Missael Vargas Velazquez, Samuel Jianjie Yeo, Dahai Luo, Vinay Tergaonkar.
      RIPK1 paradoxically orchestrates pro-survival and pro-death pathways through its scaffolding and kinase activities. Downstream of TNFR1, RIPK1 initiates the formation of two distinct multiprotein complexes: complex I for cell survival and complex IIa/IIb for apoptosis or necroptosis. However, the molecular architecture that initiates RIPK1-mediated assembly of these multiprotein signaling complexes remains unknown. Here, we elucidate the filamentous structure of the death domain of RIPK1 (RIPK1DD) at 2.5 Å resolution using cryogenic electron microscopy (cryo-EM). RIPK1DD filaments comprise three helical chains assembled via four distinct types of interactions, including a unique, hitherto undescribed Type IV interaction. Structure-guided mutagenesis of interface residues effectively disrupts RIPK1DD filament formation, impairs RIPK1 recruitment and ubiquitination within TNFR1 complex I, and abrogates TNF-induced transcriptional responses. Furthermore, death domain-mediated higher-order oligomerization drives RIPK1 autophosphorylation, which consequently licenses the assembly of complex IIa and complex IIb to execute apoptosis and necroptosis, respectively. Together, these findings reveal a critical structural basis of death domain-mediated RIPK1 oligomerization and provide fundamental mechanistic insights into RIPK1-mediated assembly of signaling complexes downstream of TNFR1.
    DOI:  https://doi.org/10.1038/s41418-026-01889-1
  6. Nucleic Acids Res. 2026 Sep 22. pii: gkag941. [Epub ahead of print]54(18):
    Establishing the molecular basis for MDA5 mutation-linked autoimmunity.
    Ling Xu, Harim Jang, Kevin Chung, Rong Guo, Alisia Pan, Anna Marie Pyle.
      Melanoma differentiation-associated protein 5 (MDA5), a member of the RIG-I-like receptor family, is a cytoplasmic sensor essential for innate antiviral immunity. MDA5 distinguishes viral RNA from host RNA in part through its ATP hydrolysis activity, which promotes filament turnover on shorter endogenous double-stranded RNAs (dsRNAs). Here, we show that the gain-of-function T331I disease-linked mutation within the ATP-binding pocket disrupts this balance, resulting in constitutive interferon signaling. Through a combination of cryo-electron microscopy (cryoEM), biochemical assays, and cellular analyses, we reveal the extensive network of interactions that precisely position ATP for catalysis in the wild-type MDA5 ATP-binding pocket and also demonstrate that the T331I mutation impairs ATPase activity, thereby stabilizing MDA5-dsRNA complexes and leading to aberrant immune activation. These findings elucidate how MDA5 ATPase activity regulates antiviral specificity and prevents autoimmunity by controlling filament stability and downstream signaling, offering a mechanistic molecular explanation for disease pathogenesis.
    DOI:  https://doi.org/10.1093/nar/gkag941
  7. PLoS One. 2026 ;21(10): e0356679
    Macrophages discriminate and sort pathogenic bacteria and apoptotic material during dual-target phagocytosis.
    Celeste Dea, Paula Arias, Sol L Moroni, Nicolás N Rolandelli, Arlinet Kierbel.
      Macrophages are central to immune homeostasis, clearing both pathogens and apoptotic cells. While these processes share some features, they differ functionally: efferocytosis of apoptotic cells is typically anti-inflammatory, whereas bacterial uptake triggers strong inflammatory responses. During infections, both targets may coexist, yet how macrophages handle such complex particles is poorly understood. Previously, we showed that Pseudomonas aeruginosa adheres to apoptotic cells, forming stable composites that can be jointly phagocytosed. Here, using quantitative confocal and live-cell imaging, we investigate how macrophages engage and internalize these dual targets. We find that macrophages employ distinct strategies depending on target composition. Apoptotic cells alone are engulfed intact within tight, actin-rich membrane cups, whereas bacteria-laden apoptotic cells induce protrusive, actin-driven extensions that navigate along the apoptotic scaffold to access bacteria. Individual bacteria are selectively extracted and internalized, while apoptotic material is internalized in a piecemeal manner. Early phagosome analysis shows that most contain either bacteria or apoptotic material alone, with mixed cargo being less frequent. These findings demonstrate that macrophages can discriminate and sort the components of complex targets during uptake. This work provides a framework for understanding how innate immune cells integrate pathogen clearance while managing apoptotic material.
    DOI:  https://doi.org/10.1371/journal.pone.0356679
  8. Res Sq. 2026 Aug 11. pii: rs.3.rs-6170527. [Epub ahead of print]
    GAPDH nuclear signaling regulates neutrophil migration and inflammatory skin responses.
    Victoriano Mulero, Joaquin Canton-Sandoval, Francisco Martinez-Morcillo, Natalia Perez-Escudero, Isabel Cabas, Beatriz Bernal-Bermudez, Anna Luciano, Juan Lozano-Gil, Alicia Martinez-Lopez, Cassia Michael, Teresa Martinez Menchon, Raul Corbalan-Velez, Belén Ferri, Maria Luisa Cayuela, Raquel Espin Palazon, Sofia de Oliveira, Diana García-Moreno.
      Neutrophils are the most abundant leukocytes and key regulators of tissue homeostasis and disease. Here we show that inhibiting Gapdh nuclear translocation limits neutrophil infiltration into inflamed skin, reduces their motility, and decreases keratinocyte hyperproliferation and cell death in a zebrafish model of skin inflammation. Wild-type Gapdh expression in neutrophils, but not a nuclear-translocation-deficient mutant, exacerbated inflammation. Pharmacological inhibition of GAPDH nuclear translocation also attenuated pathology-associated markers in human organotypic 3D skin models of inflammation. In psoriasis lesions, GAPDH levels were elevated with altered localization. Single-cell RNA-seq revealed that Gapdh nuclear translocation regulates a subset of inflammation-induced genes in neutrophils, including il4. Mechanistically, Gapdh enhances il4 transcription by promoting H3K27 acetylation at its promoter, whereas pharmacological inhibition of this pathway restores basal levels. Consistently, Il4 deficiency alleviated inflammation. These findings identify a conserved, non-canonical GAPDH signaling pathway that orchestrates chronic skin inflammation and represents a potential therapeutic target.
    DOI:  https://doi.org/10.21203/rs.3.rs-6170527/v1
  9. Elife. 2026 Oct 08. pii: RP110907. [Epub ahead of print]15
    Early recruitment of membrane-bound DNaseX to phagocytic cups in macrophages.
    Arghajit Pyne, Vivek Pandey, Subhankar Kundu, Sachie Ikegami, Xuefeng Wang.
      Macrophages engulf and degrade pathogens and cellular debris through phagocytosis. The degradation process was generally believed to occur only after phagosome internalization and maturation. Here, we report an early DNase activity at the nascent phagocytic cup (PC) prior to its closure. Using a fluorescent DNase sensor, we revealed rapid and ubiquitous DNase activity upon PC formation across various macrophage types. We further identified the responsible enzyme as the membrane-bound DNaseX, which is constitutively recruited to the PC during PC formation. F-actin polymerization was found to correlate with DNase activity in the PC, likely by promoting physical engagement of DNaseX with solid DNA materials. Functionally, we show that macrophages degrade extracellular DNA (eDNA) within bacterial biofilms through direct physical contact, clearing the eDNA structures without internalization. These findings reveal a previously unrecognized DNA degradation mechanism operating at the macrophage membrane, suitable for degrading bulky eDNA materials which cannot be directly internalized by macrophages.
    Keywords:  biofilm; cell biology; human; macrophages; neutrophil extracellular trap; nuclease activity; phagocytosis; surface nuclease sensor
    DOI:  https://doi.org/10.7554/eLife.110907
  10. FASEB J. 2026 Oct 15. 40(19): e72323
    Structural and Mechanistic Insights Into GSDME Pore Formation and Functional Regulation.
    Fei Mo, Xiaoling Chen, Jiyun Zhang, Danyang Li, Feiyue Xing, Feng-Biao Guo, Zhengyu Zhang, Changjiang Dong.
      Gasdermin E (GSDME) is a unique member of the gasdermin family linked to deafness, cancer, and neurodegenerative diseases, and mediates chemotherapy-induced pyroptosis; however, its pore-forming mechanism remains poorly understood. Here, we present cryo-EM structures of GSDME pores with oligomeric stoichiometries ranging from 23 to 29 protomers. Using mutagenesis, liposome leakage assays, and analysis of cancer-associated mutations, we identified key residues responsible for membrane binding, shallow membrane insertion, and oligomerization through three distinct structural interfaces. Molecular dynamics simulations reveal dynamic lipid recruitment and specificity: Anionic TMCL2 is selectively recruited by basic residues to facilitate shallow membrane penetration, while zwitterionic DPhPC solvates polar protein regions. Within the assembled 25-mer pore, specific lipids act as structural stabilizers to reinforce the intermolecular hydrogen bond network. Our findings support a stepwise, time-dependent mechanism underlying GSDME pore assembly. This study provides critical mechanistic insights into GSDME function and may guide the development of targeted therapeutics for cancers and neurodegenerative diseases.
    Keywords:  GSDME; cancer associated; cryo‐electron microscopy; gasdermins; molecular dynamics simulation; mutation; pore forming; pyroptosis
    DOI:  https://doi.org/10.1096/fj.202601616RRR
  11. Nat Immunol. 2026 Oct 07.
    Diverse infections transcriptionally reprogram the intestinal epithelium and epithelial-immune cell interactions.
    MIST Consortium
      The distal small intestine has a vital role in host physiology through its regulation of nutrient and fluid homeostasis. Despite being affected in Crohn's disease and serving as a major target for a range of infections, we know relatively little about the complexity of cellular responses and cell-cell communication in the ileum during infection. Here we present GutPath, an atlas of over 500,000 single cells with RNA and protein expression profiles for 91 cell states in the ileum across diverse infectious archetypes. We show that GutPath accurately captures established immune responses to infection while revealing pathogen-specific responses in enterocytes. To highlight the discovery potential of this atlas, we identify a new enterocyte transcriptional state present during Yersinia pseudotuberculosis infection that is spatially linked to bacterial load and tissue pathology. GutPath establishes a much-needed resource for the immunology community that will accelerate the study of transcriptional diversity in the cellular landscapes of the small intestine.
    DOI:  https://doi.org/10.1038/s41590-026-02665-6
  12. Cell. 2026 Oct 06. pii: S0092-8674(26)01126-8. [Epub ahead of print]
    A non-canonical function of glutathione to suppress ferroptosis via FSP1.
    Jing Han, Yu-Dan Zhang, Shuo Liu, Li Yang, Shuang-Li Sun, Ben Zhang, Ao-Kun Liu, Ling-Fan Zhu, Rong Wang, Dan-Dan Song, Xiao Zhuang, Yi-Jia Gao, Jing-Xin Li, Wen-Fei Li, Rong-Rong He, Heng-Xing Zhou, Lu Yu, Shi-Qing Feng, Ren-Jie Chai, Bo Chu.
      It is well established that glutathione (GSH) is mainly utilized by glutathione peroxidase 4 (GPX4) to diminish peroxidized phospholipids and defend against ferroptosis. However, we found that GSH robustly protects a variety of GPX4 knockout (KO) cells from ferroptosis, thus indicating that there is an alternative pathway for GSH to suppress ferroptosis. By carrying out genome-wide CRISPR-Cas9 screening, we identified that ferroptosis suppressor protein 1 (FSP1) is the key factor mediating the GPX4-independent protective effect of GSH. Mechanistically, FSP1 uses GSH to generate reduced ubiquinone, which scavenges oxidized lipids and suppresses ferroptosis. Inhibition of FSP1 abolishes this GSH-dependent ferroptosis protection both in vitro and in vivo. Distinct from NAD(P)H-mediated ubiquinone reduction, GSH-stimulated generation of reduced ubiquinone via FSP1 is independent of flavin adenine dinucleotide (FAD). Together, our work clarifies a new mechanism of GSH-mediated ferroptosis suppression, thus highlighting the potential that targeting GSH metabolism should be beneficial for ferroptosis-related diseases whether or not it is related to GPX4.
    Keywords:  FSP1; ferroptosis; glutathione metabolism; ubiquinone reduction
    DOI:  https://doi.org/10.1016/j.cell.2026.09.024
  13. Cell Rep. 2026 Oct 06. pii: S2211-1247(26)01168-X. [Epub ahead of print]45(10): 118089
    Deoxysphingolipids activate cGAS-STING and enhance antitumor immunity.
    Suchandrima Saha, Fabiola N Velazquez, Fatemeh Dehpanah, Brianna L Bergfalk, Samantha Mulkeen, Karissa J Lopez, Cungui Mao, David C Montrose.
      Deoxysphingolipids (deoxySLs) are a class of non-canonical sphingolipids that can adversely impact mitochondrial function. Mitochondrial DNA release resulting from mitochondrial disruption can activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, and in turn, promote antitumor immunity. Here, we investigated whether inducing deoxySL accumulation in colon cancer cells drives immune-specific, antitumor effects. We show that depleting serine increased deoxySLs and enhanced immune cell infiltration in colon tumors, in parallel with suppressing tumor growth. Elevating tumor deoxySL levels in mice through mutation of serine palmitoyltransferase and feeding a high alanine diet exerted similar effects, including immune-mediated tumor growth suppression. Work conducted in multiple in vitro systems identified deoxySLs as key triggers of cGAS-STING activation, an effect mediated by the release of mitochondrial DNA under mitochondrial stress. Collectively, these findings demonstrate that deoxySLs drive antitumor immunity and identify a previously unrecognized metabolic strategy for cancer therapy.
    Keywords:  CP: cancer; CP: metabolism; amino acids; chemokines; colorectal cancer; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2026.118089
  14. Nature. 2026 Oct 07.
    5-oxoETE links redox control of epithelial damage detection and resilience.
    Yanan Ma, Miklós Lengyel, King Lam Hui, Yohannes A Ambaw, Zaza Gelashvili, Leehyeon Kim, Ritchie Ly, Siyang Peng, Meysoon Quraishi, Tobias C Walther, Robert V Farese, Philipp Niethammer.
      Organisms harness oxidative stress to rapidly attract white blood cells to wound sites and to kill pathogens1-3. To this end, host tissues increase their own oxidative stress resilience and repair capacity via adaptive redox signalling4-6. Here, using live zebrafish and human cells, we identify a metabolic redox signalling mechanism that integrates oxidative immune defence with tissue adaptation. We demonstrate that DHRS7, an orphan short-chain fatty acid dehydrogenase-reductase, generates or consumes the pro-inflammatory lipid 5-oxoETE as a function of cytoplasmic NADP+/NADPH ratio. At wounds, where oxidative stress and NADP+ are high, 5-oxo-eicosatetraenoic acid (5-oxoETE) production by DHRS7 rapidly alerts antimicrobial white blood cells through the G-protein-coupled receptor OXER1. In undamaged tissue, where NADP+ is low, DHRS7 quenches unnecessary inflammation. Notably, we find that 5-oxoETE also supports epithelial redox resilience; OXER1-deficient zebrafish exhibit intestinal apoptosis, barrier disruption and microbial inflammation. Mechanistically, 5-oxoETE induces the expression of NUDIX hydrolases, which protect the cytoplasmic nucleotide pool from oxidation and prevent apoptosis in zebrafish and human intestinal cells. Thus, our data reveal a conserved mode of redox sensing and signalling-beyond classic thiol oxidation-that leverages NADPH metabolism to orchestrate the antimicrobial and pro-resilience functions of oxidative stress.
    DOI:  https://doi.org/10.1038/s41586-026-11121-2
  15. Mol Cell. 2026 Oct 06. pii: S1097-2765(26)00655-6. [Epub ahead of print]
    DNASE1L3 maintains homeostatic levels of mitochondrial DNA on the mammalian cell surface.
    Jennifer Porat, Yizhe Sun, Valentina Poli, Stefan Petkov, Karim Almahayni, Andrew Crompton, Benson M George, Francisca Nathália de Luna Vitorino, Li Yi, Carolina Bras Costa, Yitong Zhou, Hongxiu Wen, Latanya N Coke, Morgane Humbel, Sandeep K Rai, Fardin Aryan, Leon Zheng, Peter K Gregersen, George C Tsokos, Benjamin A Garcia, Yixuan Xie, Suneet Agarwal, Leonhard Möckl, Ivan Zanoni, Benjamin E Gewurz, Kim R Simpfendorfer, Ryan A Flynn.
      The extracellular space is a critical environment for discriminating self- versus non-self-nucleic acids and initiating appropriate immune responses through signaling cascades to relay information about extracellular nucleic acids. Here, we provide evidence that mitochondrial DNA is tethered to the surface of select mammalian cells through cell surface proteins and heparan sulfate proteoglycans. We demonstrate that cell surface DNA accumulates in large clusters that partially overlap with domains enriched in RNA binding proteins. Finally, we show that human and murine B cell surfaces contain DNA that can be cleared by the secreted nuclease DNASE1L3 and that patients with a DNASE1L3 missense variant associated with increased risk for autoimmune disease harbor increased levels of surface DNA on B and T cells. Taken together, this work expands the scope of cell surface nucleic acid biology and provides a mechanistic link between cell-surface molecules and DNA targeting in autoimmune disease.
    Keywords:  autoimmunity; cell surface; cell surface nucleic acids; innate immunity; mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.012
  16. Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2608835123
    MATRIN3 deficiency in human cells triggers an autoinflammatory response via cGAS-STING activation.
    Zohirul Islam, Ahsan H Polash, Colin L Sweeney, Masataka Suzawa, Bryan Chim, Sabrina Sultana, Skyler Kuhn, Nicholas Cutrona, Xiuhuai Liu, Patrick T Smith, Tibor Z Veres, Juraj Kabat, Sundar Ganesan, Amir K Foroushani, Markus Hafner, Stefan A Muljo.
      MATRIN3 (MATR3) is a broadly expressed nuclear RNA-binding protein. However, the mechanisms by which MATR3 maintains human cellular health remain poorly understood. In this study, we employed gene editing to model MATR3 deficiency in human induced pluripotent stem cells (iPSCs) and the HAP1 haploid cell line. To investigate the consequences of MATR3 loss-of-function, we profiled gene expression changes by RNA sequencing, which revealed significant upregulation of interferon-stimulated genes (ISGs) in MATR3-deficient cells, indicating activation of innate immune signaling. To elucidate the mechanism underlying ISG upregulation, we identified direct targets of MATR3 using photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP). In one of these targets, TDRD3, a gene required for R-loop metabolism in conjunction with Topoisomerase III Beta (TOP3B), MATR3 loss induced the incorporation of a 53-nucleotide-long poison exon that triggered nonsense-mediated decay and subsequent reduction in its expression. Consistent with dysfunction of the TDRD3-TOP3B complex, MATR3 loss led to the aberrant accumulation of cytoplasmic RNA-DNA hybrids, which activated the inflammatory cGAS-STING pathway. These findings uncover a previously unrecognized role of MATR3 in maintaining RNA processing fidelity and cellular homeostasis, and establish a mechanistic link between MATR3 dysfunction and innate immune activation. This molecular cascade has significant implications, hinting at a plausible disease mechanism underlying MATR3-associated neurodegenerative diseases, and other conditions of MATR3 deficiency yet to be discovered. Furthermore, these molecular insights provide potential avenues for diagnosing and treating MATR3 loss-of-function in humans.
    Keywords:  RNA splicing; RNA-binding protein; RNA–DNA hybrids; autoinflammation; interferon-stimulated genes
    DOI:  https://doi.org/10.1073/pnas.2608835123
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