bims-cediti 2026-07-26 papers

bims-cediti

Biomed News

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

Issue of 2026–07–26
nine papers selected by
Kateryna Shkarina, Universität Bonn

Caspase-mediated cleavage events hidden by secondary proteolysis during apoptosis.
The lipid A acylation pattern of Coxiella burnetii prevents detection and clearance by the non-canonical inflammasome in primary murine macrophages.
Ninjurins regulate hematopoietic stem cell amplification through canonical WNT signaling independent of plasma membrane rupture.
Mechanisms, regulation and clinical relevance of necroptosis.
Efferocytosis activates a DNMT3A-mediated oxidized DNA repair pathway to enable tissue resolution.
Mycobacterium tuberculosis infection triggers IL-1β-dependent epigenetic training in bystander macrophages.
Proteolytic activation of executioner caspase-3 and -7 regulates different physiological processes in mice.
Viral protease-initiated lytic cell death as a universal antiviral mRNA therapy.
PLA2G2F suppresses ferroptosis through phospholipid remodeling.

Protein Sci. 2026 Aug;35(8): e70724

Caspase-mediated cleavage events hidden by secondary proteolysis during apoptosis.

Fatemeh Fotouhi, Erik Gomez-Cardona, Jainilkumar Patel, Olivier Julien, Howard Fearnhead.

  Caspases are cysteine proteases that cleave specific proteins to control a range of cellular processes including cell death, inflammation, and differentiation. Proteomic approaches, like N-terminomics, have been central to identifying both cleaved proteins and where they are cleaved. We recently reported N-terminomics on differentiating and dying C2C12 myoblasts, identifying many new caspase substrates and cleavage sites. Here, we present a further analysis of this dataset demonstrating that there are caspase substrates "hidden" in our and in other N-terminomics datasets. We propose that for a subset of proteins, caspase cleavage is followed by removal of two amino acids from the neo-N-terminus by a dipeptidyl peptidase (DPP). As the peptide sequence of the neo-N-terminus is used to identify the cleavage site, this hides the caspase-mediated cleavage event. The implications of this are that N-terminomics datasets can be used to reveal hitherto unidentified caspase substrates and provide more information on cell-fate decisions. In C2C12 myoblasts, we have shown that cleavage of "hidden" substrates in apoptotic myoblasts that is absent from differentiating myoblasts (which also contain active caspase-3), suggesting that cleavage may identify apoptotic cells. A better understanding of the interplay between caspases and other proteases and their sequential action on caspase substrates may allow further elucidation of cell fate decisions.

Keywords:  BCL2L1; C2C12; JunD; N‐terminomics; Substrates; caspase‐3; cryptic; differentiation; dipeptidyl peptidase; proteolysis

DOI:  https://doi.org/10.1002/pro.70724
PLoS Pathog. 2026 Jul 24. 22(7): e1014465

The lipid A acylation pattern of Coxiella burnetii prevents detection and clearance by the non-canonical inflammasome in primary murine macrophages.

Manuela Szperlinski, Faiza Asghar, František Csicsay, Elias Schermuly, Roland Lang, Ľudovit Škultéty, Christian Berens, Katja Mertens-Scholz, Anja Lührmann.

C. burnetii is a Gram-negative, obligate intracellular bacterium and the causative agent of Q fever. The disease is either asymptomatic or manifests as a mild flu-like illness, but pneumonia or hepatitis might also occur. In most cases, the infection is self-limiting and the pathogen is cleared. In a small percentage of patients, the host immune system fails to eliminate the pathogen, potentially allowing the development of chronic Q fever months or even years after primary infection. The elimination of the bacteria, and thereby prevention of disease onset, would require an inflammatory response. Inflammasomes are multimeric protein complexes that induce a pro-inflammatory response to combat pathogens. Here we show that C. burnetii fails to induce strong activation of the non-canonical inflammasome, independently of its type IVB secretion system. However, the pathogen is unable to prevent external activation of the non-canonical inflammasome, which subsequently results in a reduction of the bacterial burden. Importantly, the acylation pattern of lipid A was identified to be involved in avoiding the activation of the non-canonical inflammasome. C. burnetii harbors a tetra-acylated lipid A. Modification of the C. burnetii lipid A to penta-/hexa-acylation in a small subpopulation resulted in increased secretion of IL1β and reduced bacterial load. Together, these results suggest that the acylation pattern of lipid A constitutes an important immune evasion strategy of C. burnetii by failing to activate the non-canonical inflammasome. In addition, evidence was provided that oxygen limitation arrests activation of the NLRP3 inflammasome in murine BMDM, which might prevent efficient elimination of bacteria under hypoxic conditions, such as in granulomas or in inflamed tissue.

DOI: https://doi.org/10.1371/journal.ppat.1014465
Nat Commun. 2026 Jul 21.

Ninjurins regulate hematopoietic stem cell amplification through canonical WNT signaling independent of plasma membrane rupture.

Juan M Lozano-Gil, Annamaria Pedoto, Lola Rodríguez-Ruiz, Francisca Alcaraz-Pérez, Diana García-Moreno, María L Cayuela, Alicia Martínez-López, Sylwia D Tyrkalska, Victoriano Mulero.

Ninjurin-1 (NINJ1), a protein required for plasma membrane rupture (PMR) during inflammasome-mediated cell death, has no known role in hematopoiesis. Here, using zebrafish and human hematopoietic stem/progenitor cells (HSPCs), we identify an evolutionarily conserved, PMR-independent function of Ninjurins in HSPC development. Ninj1 deficiency reduced HSPC, neutrophil and erythrocyte numbers, whereas PMR-deficient Ninj1 mutants demonstrated that this function is independent of PMR. Ninj1 deficiency also impaired immune cell recruitment and increased susceptibility to bacterial infection. Mechanistically, Ninj1 and Ninj2 cooperatively promoted early HSPC amplification through canonical WNT signaling. Pharmacological and genetic activation of WNT signaling rescued hematopoietic defects in Ninjurin-deficient larvae, whereas inhibition of WNT abolished the effects of Ninj1 gain of function. Human CD34⁺ HSPCs showed reduced expansion and impaired WNT signaling following NINJ1/2 deficiency, demonstrating conservation of this pathway. These findings identify Ninjurins as regulators of HSPC expansion with potential applications in regenerative medicine.

DOI: https://doi.org/10.1038/s41467-026-75917-6
Nat Rev Mol Cell Biol. 2026 Jul 21.

Mechanisms, regulation and clinical relevance of necroptosis.

Yuanxin Yang, Huipeng Jiao, Daichao Xu.

Necroptosis is a programmed lytic cell death pathway executed through mixed lineage kinase domain-like protein (MLKL)-driven plasma membrane disruption and has pivotal roles in both health and disease. Recent advances have led us to propose the classification of mammalian necroptosis into two subtypes: extrinsic and intrinsic necroptosis, which differ in their mechanisms of trigger sensing and signal integration. Extrinsic necroptosis is initiated by membrane-bound receptors, including cell-surface receptors such as tumour necrosis factor receptor 1 (TNFR1) and Toll-like receptor 4 (TLR4), as well as endosomal receptors such as TLR3, whereas intrinsic necroptosis is initiated intracellularly through sensors such as Z-DNA-binding protein 1 (ZBP1) detecting cytosolic Z-nucleic acids. In this Review, we provide an overview of the molecular mechanisms of necroptosis, highlighting the latest insights into their complex regulatory networks, execution pathways, and the growing clinical relevance and therapeutic potential of targeting necroptosis in human diseases.

DOI: https://doi.org/10.1038/s41580-026-01002-x
J Clin Invest. 2026 Jul 21. pii: e203265. [Epub ahead of print]

Efferocytosis activates a DNMT3A-mediated oxidized DNA repair pathway to enable tissue resolution.

Kleopatra Avrampou, Santosh R Sukka, David Ngai, Patrick Ampomah, Xiaobo Wang, George Kuriakose, Jacob Glass, Bernhard Dorweiler, Hanna Winter, Lars Maegdefessel, Hanrui Zhang, Aaron Viny, Ira Tabas.

  Efferocytosis, the clearance of apoptotic cells by macrophages, promotes tissue resolution. Efficient resolution requires efferocytosis-induced macrophage proliferation (EIMP) to expand pro-resolving macrophages. Here, we show that efferocytosis activates base excision repair (BER) to remove 8-OHdG from DNA, enabling EIMP. Mechanistically, efferocytosis promotes poly(ADP-ribose) polymerase-1 (PARP1) chromatin binding and PARylation to facilitate DNA repair complex assembly, and increases nuclear MTH1/NUDT1, which hydrolyzes 8-OHdG. Both processes require DNA-methyltransferase-3A (DNMT3A), which is activated during efferocytosis. Using a model where dexamethasone-induced thymocyte apoptosis triggers efferocytosis-mediated thymic repair, we showed that DNMT3A is required for increases in nuclear PARP1/MTH1, oxidized DNA suppression, EIMP in thymic macrophages, and thymic repair. We next studied a human-relevant model of atherosclerosis regression, where efferocytosis drives protective lesional fibrous cap thickening. We compared WT mice with a model of DNMT3A-clonal hematopoiesis (CH), in which loss-of-function DNMT3A mutations promote atherosclerotic disease. Atherosclerosis regression in WT mice led to decreased nuclear 8-OHdG and increases in nuclear PARP1/MTH1 and EIMP in lesional macrophages and fibrous cap thickening, all of which were impaired in DNMT3A-CH regression. These findings reveal that efferocytosis initiates a BER pathway to allow macrophage proliferation for tissue resolution, with possible therapeutic relevance to atherosclerosis regression and DNMT3A-CH.

Keywords:  Atherosclerosis; Cell biology; Macrophages; Vascular biology

DOI:  https://doi.org/10.1172/JCI203265
mBio. 2026 Jul 21. e0121426

Mycobacterium tuberculosis infection triggers IL-1β-dependent epigenetic training in bystander macrophages.

Shah-E-Jahan Gulzar, Ibrahim Umar, Bharath Saravanan, Dhruv Sheth, Arif Hussain Najar, Umer Farooq, Sahanawaz Molla, Adithi Ravikumar, Dimple Notani, Varadharajan Sundaramurthy.

  Mycobacterium tuberculosis (Mtb) remodels host cell functions to support its persistence within macrophages. While infected cells have been extensively studied, the responses of uninfected bystander macrophages in the same microenvironment remain poorly understood. Here, we demonstrate that Mtb infection triggers broad epigenetic and transcriptional reprogramming in bystander macrophages, predominantly via interleukin-1β-dependent nuclear factor-κB signaling from infected cells. These bystander cells acquire active chromatin marks, exhibit distinct gene expression profiles, and display enhanced responsiveness to subsequent immune challenges. Functionally, bystander macrophages restrict intracellular Mtb growth and also show increased responsiveness to heterologous stimuli resembling trained immunity. Our findings uncover a previously underappreciated mechanism of intercellular communication during infection, wherein Mtb-infected macrophages prime neighboring uninfected cells for enhanced defense. This work defines cytokine-mediated reprogramming of both infected and bystander cell subpopulations, and identifies bystander cells as active participants in shaping the population-wide host immune landscape. These insights have implications for understanding innate immune memory and developing strategies to modulate host defense in tuberculosis and other infections.
IMPORTANCE: This study reveals an underappreciated role for uninfected bystander macrophages in host defense against Mycobacterium tuberculosis (Mtb). We demonstrate that Mtb-infected macrophages trigger interleukin-1β-mediated epigenetic training in neighboring bystander cells, priming them for enhanced immune responses. These trained macrophages exhibit heightened antimicrobial activity and restrict Mtb growth upon subsequent infection. By uncovering a mechanism through which immune memory-like responses propagate beyond infected cells, our findings redefine the cellular scope of innate immunity during tuberculosis and identify new opportunities to boost host defense through intercellular signaling and epigenetic reprogramming.

Keywords:  H3K27 acetylation; IL-1β; bystander cells; epigenetic modifications; superinfection; trained immunity; tuberculosis

DOI:  https://doi.org/10.1128/mbio.01214-26
EMBO J. 2026 Jul 21.

Proteolytic activation of executioner caspase-3 and -7 regulates different physiological processes in mice.

Noëlle Sieg, Johanna Stachelscheid, Besarta Thaqi, Tanja Schwab, Fabian Schorn, Daniela Hahn, Adrian Georg Simon, Yuri Tolkach, Nima Abedpour, Simon E Tröder, Ingo Voigt, Felix Gaedke, Katja Wiegmann, Susanne Brodesser, Astrid Schauss, Branko Zevnik, Martin Krönke, Reinhard Büttner, Alexander Quaas, Michael Hallek, Melanie Fritsch, Hamid Kashkar.

Caspase-3 (CASP3) and caspase-7 (CASP7) are the two major executioner caspases that are proteolytically activated by upstream initiator caspases. They possess almost indistinguishable activity, which has led to the overall view that these caspases have functionally redundant roles. Here, we generate knock-in mice expressing cleavage-resistant CASP3(D175A) or CASP7(D198A). Our results show that proteolytic activation of CASP3 and CASP7 is decisive for their activity in vivo and controls redundant processes during embryonic development as combined expression of both CASP3(D175A) and CASP7(D198A) causes embryonic lethality. In adult mice, however, activation of CASP3 and CASP7 controls different processes in different tissues, without the involvement of apoptosis. While CASP7 activation is required for male fertility by controlling spermatogenesis, CASP3 activation appears crucial for lymphoid tissue development by regulating interferon signalling. Our findings shed light on emerging roles of caspases in non-apoptotic processes and provide impetus for reconsidering their involvement in physiological and pathological conditions.

DOI: https://doi.org/10.1038/s44318-026-00871-4
Cell. 2026 Jul 20. pii: S0092-8674(26)00751-8. [Epub ahead of print]

Viral protease-initiated lytic cell death as a universal antiviral mRNA therapy.

Lin Li, Xiu-Li Yan, Hao-Yang Wang, Hang-Yu Zhou, Yu-Yan Li, Wenlong Ma, Jian Li, Rong-Rong Zhang, Lu Lv, Xing-Yao Huang, Hao Du, Tian-Shu Cao, Qing Ye, Hui Zhao, Yan Fu, Byung-Ho Kang, Qiang Ding, Aiping Wu, Yi-Jiao Huang, Cheng-Feng Qin.

  While gasdermin (GSDM)-mediated pyroptosis is a potent immune effector, its antiviral potential remains largely untapped. Here, we introduce viral protease-initiated lytic cell death (VID), a universal mRNA therapeutic platform inspired by the modular architecture of GSDM and the clinical success of mRNA vaccines. By engineering gasdermin-D (GSDMD) to harbor viral protease-specific cleavage motifs, we generated VID activators (VIDAs) that selectively trigger lytic cell death in virus-infected cells. Using hepatitis A virus (HAV) as a model, lipid nanoparticle (LNP)-encapsulated VIDA mRNA abolished viral replication and shedding in vivo and mitigated liver injury through a coordinated "kill-and-alert" mechanism that primes bystander immunity. The platform's versatility was further demonstrated against Zika virus (ZIKV) and SARS-CoV-2. Leveraging a generative artificial intelligence (AI) framework, we designed de novo cleavage motifs for the SARS-CoV-2 main protease, yielding optimized VIDAs with superior antiviral potency. Collectively, our study establishes VIDA mRNA as a versatile, broadly applicable strategy for combating diverse viral threats.

Keywords:  GSDMD; VIDA; antiviral immunity; artificial intelligence; hepatitis A virus; kill-and-alert; lytic cell death; mRNA-LNP; pyroptosis; viral protease

DOI:  https://doi.org/10.1016/j.cell.2026.06.031
Nat Struct Mol Biol. 2026 Jul 22.

PLA2G2F suppresses ferroptosis through phospholipid remodeling.

Yingying Hu, Joleen Csuka, Presha Rajbhandari, Penghsuan Huang, Nicholas Carbone, Deguang Liang, Wei Gu, Alban Ordureau, Brent R Stockwell, Xuejun Jiang.

Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation, and it has emerged as a potential therapeutic vulnerability of cancer. Here we identify the secretory phospholipase PLA2G2F (phospholipase A2 group IIF) as a ferroptosis suppressor in bladder cancer and elucidate its regulation and mechanism of action. PLA2G2F functions through an intracellular mechanism by localizing to the endoplasmic reticulum to inhibit ferroptosis. Our genetic and pharmacological analyses reveal that peroxisome proliferator-activated receptor γ (PPARG), a nuclear hormone receptor and transcription factor previously implicated in ferroptosis regulation, upregulates PLA2G2F and that PPARG-mediated ferroptosis resistance is largely dependent on PLA2G2F in bladder cancer. Further, lipidomic profiling suggests that PLA2G2F preferentially acts on ether-linked phospholipids containing polyunsaturated fatty acids, thereby reducing the pool of peroxidation-prone polyunsaturated fatty acid-containing phospholipids. Together, our findings establish PLA2G2F as an endoplasmic reticulum-resident ferroptosis suppressor regulated by PPARG and show that inhibiting PPARG signaling or PLA2G2F activity can sensitize bladder cancer cells to ferroptosis induction.

DOI: https://doi.org/10.1038/s41594-026-01830-7