bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2025–07–06
thirteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction.
  2. The non-structural protein of SFTSV activates NLRP1 and CARD8 inflammasome through disrupting the DPP9-mediated ternary complex.
  3. The degree of caspase-3 aggregation determines the selectivity of arsenic-induced cell death.
  4. Ex vivo model of functioning human lymph node reveals role for innate lymphocytes and stroma in response to vaccine adjuvant.
  5. Straight A's: protein acylation in the S-activation and autophagic degradation of NOD-like receptors.
  6. Cysteine allostery and autoinhibition govern human STING oligomer functionality.
  7. TRBP modulates RLR signaling by inhibiting PKR-mediated antiviral stress granule formation.
  8. Mitochondrial thermal proteome profiling reveals aberrant activation of pyruvate dehydrogenase upon cuproptosis.
  9. Pentagalloyl glucose inhibits monosodium urate-induced inflammation and NLRP3 inflammasome formation via TAK1.
  10. Rickettsia heilongjiangensis suppresses RIPK1 kinase-mediated host cell death during the infection.
  11. The trapping of live neutrophils by macrophages during infection.
  12. Regulation of inflammatory processes by caspases.
  13. The ubiquitin E3 ligase TRIM21 suppresses type I interferon signaling via STING degradation and ameliorates systemic autoimmunity.
  1. Mol Cell. 2025 Jul 03. pii: S1097-2765(25)00505-2. [Epub ahead of print]85(13): 2610-2625.e5
    MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction.
    Zhangcheng Ding, Rui Wang, Yuhua Li, Xiaodong Wang.
      Necroptosis is a pro-inflammatory, lytic cell death executed by a pseudokinase mixed lineage kinase-like protein MLKL. Upon necroptosis induction by various inflammatory signals, MLKL is phosphorylated by receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and translocates from the cytosol to the plasma membrane, causing membrane disruption and the release of damage-associated molecular patterns (DAMPs). We report here that phosphor-MLKL also translocates to mitochondria and induces a microtubule-dependent release of mitochondrial DNA (mtDNA). The released mtDNA activates the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway, resulting in the upregulation of interferon-beta (Ifnb) expression. In a necroptosis-mediated inflammatory bowel disease (IBD) mouse model, interfering with the cGAS-STING pathway reduced inflammation and promoted intestinal recovery. Thus, MLKL induces inflammation not only in a cell non-autonomous fashion by releasing DAMP signals, but also in a cell-autonomous manner by causing mtDNA leakage into the cytosol, thereby activating the cGAS-STING pathway.
    Keywords:  IBD; MLKL; cGAS; mitochondrail DNA; mitochondria; mtDNA; necroptosis
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.005
  2. PLoS Pathog. 2025 Jul;21(7): e1013258
    The non-structural protein of SFTSV activates NLRP1 and CARD8 inflammasome through disrupting the DPP9-mediated ternary complex.
    Pan-Pan Liu, Shu-Peng Jiang, Bang Li, Wen-Tao Gui, Xiang-Rong Qin, Xue-Jie Yu.
      Inflammasomes function as immune-signaling platforms that were assembled following detection of pathogens. NLRP1 and CARD8 are related inflammasomes that use their C-terminal (CT) fragments containing a caspase recruitment domain (CARD) and the UPA domain to initiate the inflammasome. At rest, dipeptidyl peptidases 8 and 9 (DPP8/9) inhibit inflammatory CT by interacting with the function-to-find domain (FIIND) of NLRP1/CARD8 and forming an inhibitory NLRP1/CARD8-DPP9 ternary complex consisting of DPP9, full-length NLRP1/CARD8, and NLRP1/CARD8 CT. However, the specific triggers of NLRP1 and CARD8 have not yet been fully identified. Here, we report that a tick-borne bunyavirus SFTSV infection activates the NLRP1 inflammasome in primary keratinocytes and the CARD8 inflammasome in macrophages in a similar manner by targeting the ternary inhibitory complex, respectively. Mechanistically, SFTSV NSs interact with NLRP1 and CARD8 via their FIIND domains, suggesting that DPP8/9 are likely to compete for binding; on the other hand, NSs promote the degradation of DPP8 and DPP9. Both contribute to more efficient destabilization of the DPP8/9 ternary complex and release the activated CT. Moreover, CARD8 deletion promotes SFTSV replication. In conclusion, we found a novel mechanism of viral protein activation of NLRP1 and CARD8 by disrupting the DPP9-binding checkpoint.
    DOI:  https://doi.org/10.1371/journal.ppat.1013258
  3. J Toxicol Sci. 2025 ;50(7): 351-359
    The degree of caspase-3 aggregation determines the selectivity of arsenic-induced cell death.
    Yutaro Yamada, Ryo Ito, Takuya Noguchi, Shuhei Hamano, Kohei Otani, Takaya Komatsu, Yusuke Hirata, Atsushi Matsuzawa.
      It is well known that apoptosis is triggered by arsenic. Meanwhile, recent evidence has demonstrated that arsenic also induces a non-canonical form of regulated cell death (RCD) called parthanatos that is triggered by the overactivation of poly (ADP-ribose) polymerase-1 (PARP-1). Here, we provide evidence of a novel mechanistic link between parthanatos and apoptosis induced by arsenic. Exposure to sodium arsenite clearly induced parthanatos in typical cancer cell lines such as HeLa and HT1080 cells, without activation of the apoptotic cascade, including the caspase-3 activation. Of note, we observed aggregation of caspase-3 in response to sodium arsenite, which was abolished by treatment with 4-phenylbutyrate (4-PBA), a chemical chaperone that prevents protein aggregation. Interestingly, in the presence of 4-PBA, sodium arsenite induced apoptosis rather than parthanatos. These findings suggest that the disaggregation of caspase-3 allows arsenic to induce the caspase-3 activation, and subsequent apoptosis. Thus, our results show that the degree of the caspase-3 aggregation may be a critical determinant of the selectivity of sodium arsenite-induced cell death.
    Keywords:  Apoptosis; Arsenic; Caspase-3; PARP-1; Parthanatos; Protein aggregate; Sodium arsenite
    DOI:  https://doi.org/10.2131/jts.50.351
  4. Cell Rep. 2025 Jul 02. pii: S2211-1247(25)00709-0. [Epub ahead of print]44(7): 115938
    Ex vivo model of functioning human lymph node reveals role for innate lymphocytes and stroma in response to vaccine adjuvant.
    Joannah R Fergusson, Jacqueline H Y Siu, Nitya Gupta, Edward Jenkins, Eloise Nee, Sören Reinke, Tamara Ströbel, Ananya Bhalla, Shyami M Kandage, Thomas Courant, Sarah Hill, Moustafa Attar, Michael L Dustin, Alex Gordon-Weeks, Mark Coles, Calliope A Dendrou, Anita Milicic.
      Immunological processes that underpin human immune responses to therapeutics and vaccine components, such as vaccine adjuvants, remain poorly defined due to a paucity of models that faithfully recapitulate immune activation in lymphoid tissues. We describe precision-cut human lymph node (LN) slices as a functioning, architecturally preserved, full-organ cross-sectional model system. Using single-cell transcriptomics and multiplexed imaging, we explore early inflammatory response to a potent, clinically relevant liposomal vaccine adjuvant containing a TLR4-agonist and QS-21 saponin. Both TLR4 and NLRP3 inflammasome activation are involved in the direct initiation of the inflammatory response to adjuvant by monocytes and macrophages (Mon./Mac.) with secretion of interleukin (IL)-1β, but not IL-18, dependent on TLR4 signaling. Innate lymphoid cells, including natural killer cells, are indirectly activated by Mon./Mac.-produced cytokines, signaling downstream to B cells via interferon-γ secretion. Resident LN stromal populations, primed both directly and indirectly by vaccine adjuvant, are instrumental in mediating inflammatory cell recruitment, particularly neutrophils.
    Keywords:  CP: Immunology; adjuvants; ex vivo human lymph node; fluorescent imaging; mRNA-seq; single-cell transcriptomics; vaccines
    DOI:  https://doi.org/10.1016/j.celrep.2025.115938
  5. Biochem Soc Trans. 2025 Jul 04. pii: BST20253026. [Epub ahead of print]
    Straight A's: protein acylation in the S-activation and autophagic degradation of NOD-like receptors.
    Noah R Martin, Gregory D Fairn.
      Over the past decade, S-acylation has emerged as a crucial regulator of several innate immune signaling pathways, with new insights continually being gained. S-acylation, a reversible post-translational modification, involves the attachment of fatty acyl chains to cysteine residues, influencing protein localization, function, and stability. In this mini-review, we examine the accumulating evidence of the role of S-acylation in regulating nucleotide oligomerization domain (NOD)-like receptors. NOD-like receptor subfamily P3 (NLRP3), a key player in inflammasome formation, undergoes S-acylation at specific cysteine residues, which are essential for its localization to the trans-Golgi network and other organelles. Various zinc finger Asp-His-His-Cys motif-containing (zDHHC) enzymes mediate this modification, with zDHHC5 being particularly important for activation and the ability of NLRP3 to interact with never in mitosis gene A (NIMA)-related protein kinase 7 (NEK7), promoting inflammasome assembly, caspase-1 activation, and pyroptosis. Alternatively, S-acylation by zDHHC12 targets NLRP3 for chaperone-mediated autophagy, preventing excessive inflammation. NOD2, another NLR, requires S-acylation for membrane localization and effective signaling via the NF-κB and mitogen-activated protein kinase pathways in response to peptidoglycan components. Dysregulation of S-acylation in NOD2 is associated with Crohn's Disease (hypo-acylated) and Blau syndrome/early-onset sarcoidosis (hyper-acylated). Soluble NOD2 lacking S-acylation is ubiquitinated and eliminated by the autophagic pathway. This review highlights the significance of understanding the S-acylation cycle and its regulatory mechanisms in developing potential therapeutic interventions for related inflammatory diseases. We also discuss unresolved questions regarding the S-acylation of NOD2 and NLRP3, as well as the regulation of S-acylation in general.
    Keywords:   S-acylation; NF-κB; NLRP3; NOD2; ZDHHC; inflammation
    DOI:  https://doi.org/10.1042/BST20253026
  6. Nat Chem Biol. 2025 Jul 03.
    Cysteine allostery and autoinhibition govern human STING oligomer functionality.
    Rebecca Chan, Xujun Cao, Sabrina L Ergun, Evert Njomen, Stephen R Lynch, Christopher Ritchie, Benjamin Cravatt, Lingyin Li.
      The stimulator of interferon genes (STING) innate immune pathway can exacerbate inflammatory diseases when aberrantly activated, emphasizing an unmet need for STING antagonists. However, no inhibitors have advanced to the clinic because it remains unclear which mechanistic step(s) of human STING activation are crucial for inhibition of downstream signaling. Here we report that C91 palmitoylation is not universally necessary for human STING signaling. Instead, evolutionarily-conserved C64 is basally palmitoylated and is crucial for preventing unproductive STING oligomerization. The effects of palmitoylation at C64 and C91 converge on the control of intradimer disulfide bond formation at C148. Together, dynamic equilibria of these cysteine post-translational modifications allow proper STING ligand-binding domain self-assembly and scaffolding function. Given this complex landscape, we took inspiration from STING's natural autoinhibitory mechanism and identified an eight-amino-acid peptide that binds a defined pocket at the oligomerization interface, setting the stage for future therapeutic development.
    DOI:  https://doi.org/10.1038/s41589-025-01951-y
  7. Sci Rep. 2025 Jul 01. 15(1): 20678
    TRBP modulates RLR signaling by inhibiting PKR-mediated antiviral stress granule formation.
    Koji Onomoto, Monami Sakai, Miyu Watanabe, Akira Fukao, Yurika Sakamura, Mai Miyao, Takumi Tomohiro, Akio Yamashita, Toshinobu Fujiwara, Tomoko Takahashi, Kumiko Ui-Tei, Mitsutoshi Yoneyama.
      Stress granules (SGs) are dense aggregates of RNA and proteins that form in response to various cellular stresses. Virus-induced SGs, known as antiviral SGs (avSGs), play a crucial role in regulating retinoic acid-inducible gene I-like receptors (RLRs)-mediated antiviral innate immunity. However, the regulation of avSG formation remains not fully understood. In this study, we demonstrate that TAR-RNA binding protein (TRBP), an RNA silencing regulator, negatively regulates type I interferon (IFN) expression by inhibiting avSG formation in response to RNA virus infection. Overexpression of TRBP inhibits both IFN-β promoter activity and avSG formation following viral infection or the viral RNA mimic, polyinosinic-polycytidylic acid transfection. TRBP knockout cells exhibit enhanced phosphorylation and activation of IFN regulatory factor-3 (IRF-3) and increased IFN-β mRNA expression compared to wild-type cells. Additionally, depletion of G3BP1 and G3BP2, which are essential for SG formation, abolishes the inhibitory effect of TRBP on IRF-3 phosphorylation. Mechanistically, TRBP physically interacts with double-stranded RNA (dsRNA)-dependent protein kinase R (PKR), a key kinase involved in avSG formation, via its dsRNA-binding domains, and inhibits PKR activation. In summary, our findings reveal a novel function for TRBP as a negative regulator of RLR-mediated signaling through PKR-dependent inhibition of avSG formation.
    Keywords:  Antiviral innate immunity; IFN; RLR; Stress granule; TRBP
    DOI:  https://doi.org/10.1038/s41598-025-07121-3
  8. Cell Rep. 2025 Jul 02. pii: S2211-1247(25)00708-9. [Epub ahead of print]44(7): 115937
    Mitochondrial thermal proteome profiling reveals aberrant activation of pyruvate dehydrogenase upon cuproptosis.
    Zongyu Huang, Yanjun Liu, Ya Zeng, Jun Wang, Siyuan Sun, Chris Soon Heng Tan, Peng R Chen.
      Cuproptosis, a copper-induced form of regulated cell death, holds therapeutic promise in cancer but remains mechanistically unclear. We developed Mito-TPCA, a mitochondrial thermal proximity coaggregation strategy combining enzyme-catalyzed proteome labeling with thermal profiling, to map mitochondrial protein-protein interaction dynamics during cuproptosis. This approach revealed that copper disrupts the association of pyruvate dehydrogenase kinases (PDKs) with the pyruvate dehydrogenase (PDH) complex by targeting lipoyl domains, triggering PDH dephosphorylation and aberrant activation. We demonstrate that this PDH activation is a key driver of cuproptosis and contributes to the heightened susceptibility of cancer cells. These findings establish PDH dephosphorylation/activation as a central mechanism of cuproptosis and a potential anti-cancer therapeutic target. Mito-TPCA offers a versatile platform to study mitochondrial protein complex dynamics in live cells.
    Keywords:  CP: Metabolism; CP: Molecular biology; cancer cell susceptibility; cuproptosis; mitochondrial thermal proteome; proximity labeling; pyruvate dehydrogenase aberrant activation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115937
  9. Am J Physiol Cell Physiol. 2025 Jul 02.
    Pentagalloyl glucose inhibits monosodium urate-induced inflammation and NLRP3 inflammasome formation via TAK1.
    Paul M Panipinto, Guihua E Yue, Bhagwat Prasad, Salahuddin Ahmed.
      Monosodium urate (MSU)-induced inflammation is caused by the deposition of MSU crystals in the joints and periarticular tissues under conditions of hyperuricemia. These deposits can activate joint resident macrophages which form the NOD-, LRR- and pyrin-containing protein 3 (NLRP3) inflammasome, cleaving pro-IL-1β and causing inflammation. The present study investigated the anti-inflammatory properties of a polyphenolic compound pentagalloyl glucose (PGG) in MSU-induced inflammation. Pretreatment of THP-1 monocyte-derived macrophages with PGG (0.1-10 μM) caused a dose-dependent inhibition of MSU-induced TAK1184/187 and NF-κB p65 phosphorylation. PGG significantly reduced the production of pro-IL-1β during the priming phase, which correlated with its inhibition of NLRP3 inflammasome formation as observed by the reduced ASC speck formation and a consequent decrease in IL-8, MCP-1, and IL-1β production. Using liquid chromatography/mass spectrometry (LC-MS/MS)-based untargeted phosphoproteomics analysis, we discovered 3,919 unique phosphorylation sites modulated by MSU. Of 667 phosphosites upregulated by MSU, PGG selectively suppressed 218, a TAK1 inhibitor (5Z-7-oxozeaenol; 5Z7o) inhibited 134, and both inhibitors commonly inhibited 181. Conversely, 443 total phosphosites were suppressed by MSU which were reduced to only 139 by PGG and 132 by 5Z7o. Administration of PGG (30 mg/kg; intraperitoneally) significantly suppressed MSU-induced paw inflammation in C57BL/6J mice and reduced the time to flare resolution. These findings showed that PGG significantly reduced MSU-induced proinflammatory mediators and inhibited the formation of NLRP3 inflammasomes by primarily targeting the TAK1 pathway. Our finding suggests that dietary supplementation of PGG may help reduce the onset and severity of acute gout flares.
    Keywords:  Inflammasome; Interleukin-1; TAK1; gout; pentagalloyl glucose
    DOI:  https://doi.org/10.1152/ajpcell.00673.2024
  10. Infect Immun. 2025 Jul 03. e0015825
    Rickettsia heilongjiangensis suppresses RIPK1 kinase-mediated host cell death during the infection.
    Maozhang He, Qingyin Shi, Yu Xin, Shurui Zheng, Yan Liu, Kehan Xu.
      Spotted fever group Rickettsia (SFGR) poses a significant challenge in the field of tick-borne diseases, characterized by its obligate intracellular lifestyle and its ability to disrupt various host cellular pathways. A deeper understanding of Rickettsia's interactions with immune signaling is crucial for the development of novel therapeutic strategies. While previous research has shown that SFGR infection manipulates host cell death responses, the specific effects on receptor-interacting protein kinase 1 (RIPK1)-mediated multiple cell death pathways-collectively referred to as PANoptosis-remain poorly understood. In this study, we reveal that infection with Rickettsia heilongjiangensis suppresses RIPK1 kinase-dependent apoptosis and necroptosis in human microvascular endothelial cells (HMEC-1). However, mitochondria-dependent apoptosis during the late stages of infection is essential for bacterial replication. Interestingly, inhibition of caspase-8 does not sensitize Rickettsia-infected host cells to necroptosis. Transcriptomic analysis further reveals that Rickettsia infection upregulates the host tumor necrosis factor (TNF) and NF-κB signaling pathways, which subsequently suppress RIPK1 kinase activity and contribute to the inhibition of host cell death. These findings provide new insights into the molecular mechanisms by which Rickettsia evades host defenses.
    Keywords:  PANoptosis; Rickettsia; caspase; receptor interacting protein kinase 1 (RIPK1); tumor necrosis factor (TNF)
    DOI:  https://doi.org/10.1128/iai.00158-25
  11. Cell Death Dis. 2025 Jul 03. 16(1): 488
    The trapping of live neutrophils by macrophages during infection.
    Kelley N Cooper, Marina Terekhova, Barbara Potempa, Ana D'Aubeterre, Jerome Timbol, Si An Chen, Antoine Dufour, Shunying Jin, Maxim N Artyomov, Jan Potempa, Juhi Bagaitkar.
      Neutrophils are highly abundant in the oral mucosal tissues, and their balanced activation and clearance are essential for immune homeostasis. Here, we demonstrate that neutrophils infected with the bacterial pathogen Porphyromonas gingivalis (Pg) are captured alive by macrophages in a manner that bypasses all known receptor-ligand interactions involved in the phagocytosis of either live or dead cells. Mechanistically, upon interaction with Pg, or its protease RgpB (gingipains), live neutrophils undergo rapid remodeling of their proteomes, generating neoepitopes. N-terminomics-based proteomic profiling identified multiple RgpB cleavage sites on several azurophilic granule proteins that are translocated to the surface of live neutrophils via low-level degranulation and activate macrophage αMβ2 integrin receptors, thus mediating internalization of non-apoptotic neutrophils within macrophage phagosomes. Macrophages with entrapped live neutrophils exhibit phenotypic and transcriptional reprogramming, consistent with inflammatory outcomes in vitro and in vivo. In contrast to the immunosuppressive outcomes associated with efferocytosis of apoptotic neutrophils, live neutrophil entrapment failed to fully activate several catabolic and metabolic processes and exhibited a defective activation of PPAR-γ mediated pro-resolution pathways, thereby promoting bacterial persistence and hindering the resolution of inflammation. Thus, our data demonstrate a novel immune subversion strategy unique to Pg and reveal a previously unknown mode of live neutrophil sequestration into macrophages during an infection.
    DOI:  https://doi.org/10.1038/s41419-025-07808-5
  12. Nat Rev Mol Cell Biol. 2025 Jul 02.
    Regulation of inflammatory processes by caspases.
    Manuel Beltrán-Visiedo, Ruth Soler-Agesta, Kristopher A Sarosiek, Douglas R Green, Lorenzo Galluzzi.
      Historically, mammalian caspases (a group of cysteine proteases) have been catalogued into two main families based on major biological function: inflammatory caspases and apoptotic caspases. Accumulating evidence from preclinical models, however, argues against such a clearcut distinction, for two main reasons. First, at least in mammals, apoptotic caspases are generally dispensable for cells to succumb to apoptotic stimuli but instead regulate the kinetic and microenvironmental manifestations of the cellular demise in the context of a complex interplay with other cell death pathways. Second, most (if not all) mammalian caspases have evolved into positive or negative regulators of inflammatory processes, either directly or via their ability to control apoptotic and non-apoptotic cell death modalities. Here we discuss the molecular mechanisms through which mammalian caspases regulate inflammation, with emphasis on the ability of apoptotic caspases to suppress inflammatory responses in support of preserved organismal homeostasis.
    DOI:  https://doi.org/10.1038/s41580-025-00869-6
  13. Exp Mol Med. 2025 Jul 03.
    The ubiquitin E3 ligase TRIM21 suppresses type I interferon signaling via STING degradation and ameliorates systemic autoimmunity.
    Da Som Kim, Youngjae Park, George C Tsokos, Mi-La Cho, Seung-Ki Kwok.
      Tripartite motif-containing 21 (TRIM21) is a cytoplasmic protein with E3 ubiquitin ligase activity. Although autoantibodies against TRIM21 are frequently detected in patients with systemic lupus erythematosus (SLE), its role in disease pathogenesis remains unclear. Here we demonstrate that TRIM21 directly interacts with the stimulator of interferon genes (STING) to regulate type I interferon (IFN) production. In both induced and spontaneous murine models of lupus, TRIM21 deficiency exacerbated lupus-like pathology and heightened IFN production after STING activation. By contrast, TRIM21 overexpression attenuated autoimmunity in lupus-prone mice. Mechanistically, TRIM21 binds to STING and promotes its degradation via the ubiquitin-proteasome pathway. In patients with SLE, TRIM21 expression levels inversely correlated with STING expression, type I IFN levels and autoantibody titers. These findings suggest that targeting the TRIM21-STING axis may offer a therapeutic strategy to reduce type I IFN production in SLE.
    DOI:  https://doi.org/10.1038/s12276-025-01490-5
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