bims-cediti 2026-01-04 papers

bims-cediti

Biomed News

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

Issue of 2026–01–04
thirteen papers selected by
Kateryna Shkarina, Universität Bonn

LPS-induced structural reorganization and polymerization drive noncanonical inflammasome activation.
14-3-3ε-dependent deubiquitination and translocation of NLRP3 activates the inflammasome during sepsis.
Multimodal cell death drives the immunopathogenesis of RSV infection.
A CLOCK-targeting lncRNA induces trained immunity against tuberculosis.
Detection of Ferroptosis by Liperfluo and BODIPY™ 581/591 C11.
ETS Translocation Variant 5 Negatively Modulates Innate Immunity to Facilitate Epstein-Barr Virus Reactivation.
Intrinsic OASL expression governs heterogeneity in interferon induction during influenza A virus infection.
Heat stress activates the coagulation cascade through Z-DNA-binding protein 1-dependent necroptosis.
Ebola virus matrix protein VP40 triggers inflammatory responses linked to the ebolavirus virulence.
Senescent cells secrete chromatin components via senescence-associated extracellular particles.
Legionella effector Ceg10 acetylates RPS20 to inhibit host translation and induce cell cycle arrest.
Caspase-2 deficiency drives pathogenic liver polyploidy and increases age-associated hepatocellular carcinoma in mice.
The Role of Posttranslational Modifications During Ebola Virus Infection.

Sci Adv. 2026 Jan 02. 12(1): eadz4623

LPS-induced structural reorganization and polymerization drive noncanonical inflammasome activation.

Chengliang Wang, Philip Lacey, Tian Tian, Evelyn Teran, Maham Liaqat, Sonia Shivcharan, Patience Shumba, Jie He, Vijay A Rathinam, Vicki H Wysocki, Jianbin Ruan.

The noncanonical inflammasome, mediated by murine caspase-11 and its human orthologs caspase-4 and caspase-5, detects intracellular lipopolysaccharide (LPS) and triggers pyroptotic cell death. Upon LPS binding through their amino-terminal caspase activation and recruitment domains (CARDs), these inflammatory caspases oligomerize and activate. However, how LPS binding drives caspase-4/11 activation remains unclear. Here, we show that caspase-4/11 CARDs are intrinsically unstructured in their resting state and adopt an α-helical conformation upon LPS engagement. This structural rearrangement promotes CARD oligomerization, with electron-capture charge reduction-coupled native mass spectrometry and other techniques illustrating that hexa-acylated LPS induces the formation of large oligomers composed of eight or more protomers, whereas underacylated lipids trigger smaller assemblies. Using hydrogen-deuterium exchange mass spectrometry and cross-linking mass spectrometry, we identified a hydrophobic cleft critical for LPS binding and potential intersubunit interfaces that facilitate oligomerization. These findings uncover key structural features underlying LPS recognition and activation of the noncanonical inflammasome, providing mechanistic insight into an essential arm of the innate immune response.

DOI: https://doi.org/10.1126/sciadv.adz4623
JCI Insight. 2026 Jan 09. pii: e192970. [Epub ahead of print]11(1):

14-3-3ε-dependent deubiquitination and translocation of NLRP3 activates the inflammasome during sepsis.

Xingyu Li, Siqi Ming, Can Cao, Yating Xu, Jingxian Shu, Ning Tan, Xi Huang, Yongjian Wu.

  The activation of the NLRP3 inflammasome is a pivotal step in hyperinflammation in sepsis; however, the regulatory mechanisms underlying its activation are not fully understood. In this study, we found that 14-3-3ε facilitates NLRP3 inflammasome activation by enhancing NLRP3 K63 deubiquitination and promoting its translocation to the mitochondria-associated ER membranes (MAMs) for full activation. Mass spectrometry revealed that 14-3-3ε binds to NLRP3 in macrophages during sepsis. Plasma 14-3-3ε levels were elevated in patients with sepsis and were positively associated with disease severity. 14-3-3ε promoted NLRP3 inflammasome activation by facilitating NLRP3 aggregation and NLRP3-ASC assembly. The interaction between 14-3-3ε and NLRP3 was dependent on phosphorylation at the S194 site of NLRP3 NACHT domain. The NLRP3-14-3-3ε interaction promoted K63 deubiquitination and enhanced the translocation of NLRP3 to MAMs, which is necessary for full activation of NLRP3 inflammasome. Furthermore, macrophage-conditional KO of 14-3-3ε or treatment with BV02, a 14-3-3 inhibitor, improved the survival rate and alleviated organ injuries in septic mice. Taken together, our data indicate that 14-3-3ε functions as a positive regulator of the NLRP3 inflammasome and could be a target for sepsis treatment.

Keywords:  Infectious disease; Inflammation; Macrophages

DOI:  https://doi.org/10.1172/jci.insight.192970
Front Immunol. 2025 ;16 1740904

Multimodal cell death drives the immunopathogenesis of RSV infection.

Tianxiang Yang, Zhizhong Mi, Zhaolong Li.

  Respiratory syncytial virus (RSV) is a major cause of severe respiratory tract infections in infants, older adults, and immunocompromised individuals. Despite decades of research, effective therapies are limited, largely due to an incomplete understanding of how infected cells and immune responses interact to shape disease outcomes. Recent evidence indicates that RSV activates multiple regulated cell death (RCD) programs-including apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-associated cell death which interact through shared molecular mediators to form a multimodal cell death (MMCD) network. This integrated system regulates the balance between viral clearance and immunopathological injury. Central mediators such as caspase-8, RIPK3, and NLRP3 act as molecular hubs coordinating these death programs and amplifying inflammatory responses. Understanding how MMCD shapes RSV immunopathogenesis provides a unified framework linking cell death to immune dysfunction. This review summarizes recent progress in elucidating the MMCD network, highlights its role in death-inflammation feedback loops, and discusses potential strategies for therapeutic modulation. Conceptualizing RSV disease through the lens of MMCD may guide the development of precision interventions that restore immune homeostasis while preserving antiviral defense.

Keywords:  NLRP3 inflammasome; RSV; caspase-8; immune amplification; multimodal cell death; regulated cell death; therapeutic targeting

DOI:  https://doi.org/10.3389/fimmu.2025.1740904
Cell Host Microbe. 2025 Dec 30. pii: S1931-3128(25)00521-9. [Epub ahead of print]

A CLOCK-targeting lncRNA induces trained immunity against tuberculosis.

Shanshan Yu, Qiyao Chai, Zhe Lu, Changgen Qiu, Yanzhao Zhong, Yiru Wang, Zehui Lei, Lihua Qiang, Yingxu Fang, Xinwen Zhang, Bingxi Li, Mengqiu Gao, Lingqiang Zhang, Gong Cheng, Jing Wang, Cui Hua Liu, Yu Pang.

  Trained immunity confers innate immune memory via metabolic and epigenetic reprogramming, yet the intercellular mediators regulating this process in host defense remain largely elusive. Here, through plasma exosomal profiling of tuberculosis (TB)-resistant individuals, we identify a trained immunity-inducing long non-coding RNA (lncRNA), termed tuberculosisresister-derived CLOCK regulator 1 (TRCR1). Mechanistically, exosome-derived TRCR1 collaborates with the RNA-binding protein FXR2 to stabilize CLOCK mRNA by forming lncRNA-protein-mRNA complexes in monocytes, thus enhancing circadian regulator CLOCK expression and promoting CLOCK-mediated histone H3 acetylation (K9/K14) at immune gene promoters, ultimately establishing epigenetic memory-mediated antimicrobial activity. We further reveal that Mycobacterium tuberculosis (Mtb)-secreted protein MPT53 induces lung epithelial cells to release TRCR1-enriched exosomes. In mice, TRCR1 training strengthens host anti-Mtb immunity and improves Bacille Calmette-Guérin (BCG) vaccine efficacy. Collectively, our findings unveil an intercellular TRCR1-FXR2-CLOCK axis driving trained immunity at the lung-systemic immune interface, providing a strategy for refining BCG vaccination and preventing infectious diseases.

Keywords:  CLOCK; exosome; long non-coding RNA; resister; trained immunity; tuberculosis

DOI:  https://doi.org/10.1016/j.chom.2025.12.002
Methods Mol Biol. 2026 ;2983 135-142

Detection of Ferroptosis by Liperfluo and BODIPY™ 581/591 C11.

Cristina Aguilar Flores, Wan Seok Yang.

  Ferroptosis is a unique form of regulated cell death characterized by the toxic buildup of lipid peroxides in plasma membranes. Uncontrolled ferroptosis has been linked to various pathological conditions, including cancer progression, neurodegeneration, kidney damage, ischemia/reperfusion injury, and T-cell immunity. In this article, we present a method for detecting ferroptosis by measuring lipid peroxides in cellular membranes with the Liperfluo and BODIPY-C11 probes. The potential role of ferroptosis in immune-modulatory cells can also be assessed using this approach.

Keywords:  BODIPY-C11; Erastin, RSL3; Ferroptosis; Liperfluo; Lipid peroxides

DOI:  https://doi.org/10.1007/978-1-0716-4901-5_13
J Med Virol. 2026 Jan;98(1): e70783

ETS Translocation Variant 5 Negatively Modulates Innate Immunity to Facilitate Epstein-Barr Virus Reactivation.

Xuefei Liao, Mengdi Chen, Li Yang, Mingjuan Jiang, Yujie Xin, Huirong Yan, Qingshuang Qin, Jianhong Lu.

  Epstein-Barr virus (EBV) is a member of the gamma-herpesvirus subfamily that is prevalent in the human population. There are two phases of EBV infection: latent infection and lytic infection. During lytic reactivation, host innate immune responses are activated to restrict EBV replication. Here, we identified ETS translocation variant 5 (ETV5) as a negative regulator of innate immune responses to facilitate EBV reactivation. ETV5 expression was upregulated by the EBNA1/BRD7 axis, which had been previously described by us, during EBV latent infection. When EBV was induced into lytic replication, the expression of ETV5 was further increased, and ETV5 overexpression dramatically enhanced the lytic replication of EBV. Mechanistically, upon EBV reactivation, the overexpression of ETV5 suppressed the activation of TANK-binding kinase 1 and interferon regulatory factor 3 (IRF3), as well as the transcription of interferon beta (IFNB1) gene and interferon-stimulated genes (ISGs). The effect of ETV5 knockdown could be reversed by an inhibitor of innate immunity pathway. These findings position ETV5 as a critical accelerator of EBV reactivation through immune evasion, revealing new therapeutic targets for managing EBV-associated diseases.

Keywords:  ETV5; Epstein‐Barr virus; innate immune response; reactivation

DOI:  https://doi.org/10.1002/jmv.70783
Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2509560123

Intrinsic OASL expression governs heterogeneity in interferon induction during influenza A virus infection.

Joel Rivera-Cardona, Tarun Mahajan, Elizabeth A Thayer, Neeharika R Kakuturu, Qi Wen Teo, Joseph Lederer, Elizabeth F Rowland, Kyle Heimburger, Jiayi Sun, Cera A McDonald, Clayton K Mickelson, Ryan A Langlois, Nicholas C Wu, Olgica Milenkovic, Sergei Maslov, Christopher B Brooke.

  Effective control of viral infection requires rapid induction of the innate immune response, especially the type I and type III interferon (IFN) systems. Despite the critical role of IFN induction in host defense, numerous studies have established that most cells fail to produce IFNs in response to viral stimuli. The specific factors that govern cellular heterogeneity in IFN induction potential during infection are not understood. To identify specific host factors that license some cells but not others to mount an IFN response to viral infection, we developed an approach for analyzing temporal scRNA-seq data of influenza A virus (IAV)-infected cells. This approach identified the expression of several interferon stimulated genes (ISGs) within preinfection cells as correlates of IFN induction potential of those cells, postinfection. Validation experiments confirmed that intrinsic expression of the ISG OASL is essential for robust IFNL induction during IAV infection. Altogether, our findings reveal an important role for intrinsic expression of ISGs in promoting IFN induction and provide insights into the mechanisms that regulate cell-to-cell heterogeneity in innate immune activation.

Keywords:  antiviral response; cellular heterogeneity; influenza A virus; interferon; scRNA-seq

DOI:  https://doi.org/10.1073/pnas.2509560123
Blood. 2026 Jan 02. pii: blood.2025030764. [Epub ahead of print]

Heat stress activates the coagulation cascade through Z-DNA-binding protein 1-dependent necroptosis.

Fanglin Li, Jinxiu Li, Jian Shi, Xinyu Yang, Ting Zhang, Hao Liu, Fengjie Wang, Xiao Yan, Qiuli He, Long Wu, Yong Zou, Yiting Tang, Erhua Wang, Yanjun Zhong.

Heatstroke, a severe hyperthermic condition, is characterized by a core body temperature exceeding 40℃ and multiple organ dysfunction syndrome (MODS) with an extremely high mortality rate. Despite advances in identifying heatstroke-induced cell death pathways, the molecular cascades that bridge heat-induced cell death to MODS and mortality are not yet fully characterized. Our findings demonstrate that Z-DNA binding protein 1 (ZBP1)-triggered disseminated intravascular coagulation critically drives MODS and fatal outcomes in heatstroke. Heat stress activates ZBP1-dependent necroptosis, promoting tissue factor (TF) release and phosphatidylserine (PS) externalization. Genetic knockout of ZBP1 or its downstream necroptotic effectors, reduction of global TF expression, suppression of PS exposure, or pharmacological inhibition of the coagulation cascade attenuates heat stress-induced coagulation activation, organ injury, and death. Comparable results are obtained in heat-stressed mice with conditional knockout of ZBP1 in hematopoietic or myeloid lineages. Overall, our study reveals the critical role of ZBP1-mediated necroptosis in bridging heat stress and coagulation dysfunction.

DOI: https://doi.org/10.1182/blood.2025030764
Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2508194123

Ebola virus matrix protein VP40 triggers inflammatory responses linked to the ebolavirus virulence.

Satoko Yamaoka, Zeineb M'Hamdi, Lin Wang, Vaille A Swenson, Kristin L McNally, Shao-Chia Lu, Reema Singh, Stephanie L Saundh, Brady N Zell, Sonja M Best, Michael A Barry, Angela L Rasmussen, Hideki Ebihara.

  Uncontrolled systemic inflammatory responses are a critical pathological feature of fatal Ebola virus (EBOV) infection. While some inflammatory responses may originate from mononuclear phagocytes (MNPs), nonimmune cells vastly outnumber MNPs and may be an important source of inflammation. Here, we demonstrated that highly virulent EBOV induced a high and sustained pro-inflammatory response compared to less virulent ebolaviruses in non-MNPs through TLR4-independent NF-κB activation. We identified the EBOV matrix protein VP40 as a potent activator of NF-κB in non-MNPs, whose intrinsic inflammatory activation ability is higher than VP40 proteins from less virulent ebolaviruses. This suggests that VP40 is a virulence determinant inducing distinct degrees of pro-inflammatory responses among ebolaviruses. Mechanistically, VP40 activated the NF-κB signaling pathway, primarily via TNFR1 using a ligand-independent mechanism. These findings reveal mechanisms that may drive systemic inflammation and promote EBOV pathogenesis, suggesting potential therapeutic strategies to mitigate immune dysregulation in severe EBOV infections.

Keywords:  NF-κB; filovirus; inflammation; matrix protein VP40; virulence

DOI:  https://doi.org/10.1073/pnas.2508194123
bioRxiv. 2025 Dec 16. pii: 2025.12.12.694055. [Epub ahead of print]

Senescent cells secrete chromatin components via senescence-associated extracellular particles.

Sviatlana Zaretski, Jose L Nieto Torres, Xue Lei, John P Nolan, Malene Hansen, Peter D Adams.

Senescent cells influence their surroundings through the senescence-associated secretory phenotype (SASP), an assortment of secreted molecules and macromolecular complexes. Among SASP's intracellular drivers are cytoplasmic chromatin fragments (CCFs), nuclear-derived DNA that activates the pro-inflammatory cGAS/STING pathway. While autophagy contributes to CCFs degradation, the full repertoire of CCF fates and signaling functions remains unclear. Here, we show that senescent cells release CCF components, ɣH2AX and double-stranded DNA (dsDNA), into the extracellular space via an ESCRT-independent multivesicular body pathway. Secreted CCF components localize to extracellular particles exhibiting an unusual "popcorn"-like morphology, distinct from canonical small extracellular vesicles. Notably, inhibition of autophagy enhances secretion of CCF components and particles, suggesting an inverse relationship between intracellular clearance and extracellular release. A fraction of CCF-containing extracellular particles activates cGAS-STING signaling in non-senescent proliferating cells and is enriched in the circulation of aged mice, pointing to a previously unrecognized mode of extracellular signaling by senescent cells.

DOI: https://doi.org/10.64898/2025.12.12.694055
Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2517995123

Legionella effector Ceg10 acetylates RPS20 to inhibit host translation and induce cell cycle arrest.

Jiajia Gao, Wenwen Xu, Ziyi Zhou, Lixin Lu, Zhenhuang Ge, Weiqiang Wang, Yongjun Lu, Honghua Ge.

  Legionella pneumophila, the causative agent of Legionnaires' disease, utilizes a type IV secretion system (T4SS) to translocate effectors into host cells, modulating diverse cellular processes to create a replication-permissive niche. Here, we characterize Ceg10, a T4SS-translocated effector, as a nucleus-targeting acetyltransferase that interferes with host ribosome biogenesis and cell cycle progression. Structural analysis reveals that Ceg10 harbors a conserved Cys-His-Asp (CHD) catalytic triad required for its acetyltransferase activity. Upon nuclear import mediated by the host transport adaptor HEATR3, Ceg10 selectively acetylates the ribosomal protein RPS20 at Thr64, Thr65, and Arg66, which have not been annotated as posttranslational modification sites. This acetylation impairs RPS20's interaction with RPS29 and 18S rRNA, two components critical for 40S ribosomal subunit assembly, leading to translation inhibition and G1/S cell cycle arrest. These host perturbations are essential for efficient early-stage intracellular replication of L. pneumophila. Our findings identify a distinct mechanism by which a bacterial effector co-opts nuclear import machinery and directly modifies ribosomal proteins to subvert host biosynthesis and cell cycle control, highlighting ribosomal protein acetylation as a hitherto unrecognized role in host-pathogen interactions.

Keywords:  Legionella pneumophila; cell cycle arrest; protein acetylation; ribosomal protein RPS20; type IV secretion system

DOI:  https://doi.org/10.1073/pnas.2517995123
Sci Adv. 2026 Jan 02. 12(1): eaeb2571

Caspase-2 deficiency drives pathogenic liver polyploidy and increases age-associated hepatocellular carcinoma in mice.

Loretta Dorstyn, Yoon Lim, Jack Scanlan, Emma McLennan, Dylan De Bellis, Michael Katschner, John Finnie, Samantha Emery-Corbin, Jumana Yousef, Laura F Dagley, Chung H Kok, Sonia S Shah, Chiaki Takahashi, Mark A Febbraio, Sharad Kumar.

Hepatocyte polyploidization promotes liver homeostasis by enhancing resistance to cellular stress. Caspase-2, a proapoptotic protease, restricts polyploidization by deleting polyploid and aneuploid cells. While caspase-2 protects against diet-induced hepatic injury, it also acts as a tumor suppressor by controlling genomic instability and oxidative stress. To investigate these roles, we assessed hepatic ploidy dynamics, liver damage, and age-associated tumorigenesis in caspase-2-deficient and catalytically inactive mutant mice. We found that caspase-2 loss promotes early-onset hepatocyte hyperpolyploidy, accompanied by progressive liver inflammation, fibrosis, oxidative liver damage, ferroptosis, and higher incidence of spontaneous hepatocellular carcinoma in aged animals. Proteomic profiling revealed a pathogenic polyploidy-associated signature associated with caspase-2 deficiency and increased predisposition to liver disease and malignancy. These findings establish caspase-2 enzymatic activity as a critical regulator of hepatic genome stability and preventing age-related liver cancer that strongly argue against therapeutic caspase-2 inhibition as a strategy for managing liver injury or cancer risk.

DOI: https://doi.org/10.1126/sciadv.aeb2571
Viruses. 2025 Dec 18. pii: 1640. [Epub ahead of print]17(12):

The Role of Posttranslational Modifications During Ebola Virus Infection.

Joaquin Moreno-Contreras, Yoatzin Peñaflor-Tellez, Ricardo Rajsbaum.

  Orthoebolaviruses (OEV) are highly pathogenic viruses responsible for the Ebola virus disease (EVD). To establish a successful infection, OEV hijacks the host cell machinery, which in turn responds to infection by activating cellular antiviral pathways. These processes are regulated via post-translational modifications (PTMs) of both cellular and viral proteins. The most common PTMs include phosphorylation, ubiquitination, acetylation, methylation, and glycosylation. These modifications regulate stability, activity, and interactions between proteins that control the immune response, cell metabolism, and cell death, among others. PTMs are critical during the viral replication cycle as they can be either proviral, facilitating adequate virus replication inside the infected cell, or antiviral, most commonly hindering essential viral processes such as viral genome transcription or replication. Here, we review the different roles of PTMs known to occur during OEV infection in both viral and cellular proteins. Understanding how OEV modulates the fate of host cell proteins through specific PTMs can provide a basis for the development of novel therapeutic strategies.

Keywords:  innate immune system; orthoebolaviruses; phosphorylation; post-translational modifications; replication cycle; ubiquitination

DOI:  https://doi.org/10.3390/v17121640