bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2025–12–28
six papers selected by
Kateryna Shkarina, Universität Bonn
  1. Resident alveolar macrophages are highly susceptible to the induction of RIPK1/RIPK3-mediated necroptosis which promote efficient pulmonary immune response.
  2. A TAK1 cytokine toxicity checkpoint controls anti-cancer immunity.
  3. Decoding necrosome assembly: harmonizing signal amplification and attenuation through optimal RIP3 stoichiometry.
  4. pH-regulated nuclear F-actin assembly during ferroptosis.
  5. Primate-specific adaptation of Ku protects transcriptomic integrity by suppressing Alu-mediated alternative splicing.
  6. Optogenetic engineering of BAX to control mitochondrial permeabilization and attenuate apoptosis in cells.
  1. Cell Death Dis. 2025 Dec 22.
    Resident alveolar macrophages are highly susceptible to the induction of RIPK1/RIPK3-mediated necroptosis which promote efficient pulmonary immune response.
    Takumi Adachi, Kazufumi Matsushita, Koubun Yasuda, Masakiyo Nakahira, Mai Imasaka, Michihiko Sugimoto, Zhuohao Yang, Kouji Kobiyama, Tomoya Hayashi, Ken J Ishii, Yasuo Yoshioka, Masaki Ohmuraya, Yoshitaka Shirasaki, Etsushi Kuroda.
      Alveolar macrophages (AMs) play a crucial role in protecting the lungs from pathogens by inducing immunogenic cell death (ICD). However, the type of cell death that effectively induces protective immunity remains to be fully understood. In our investigation of the mechanisms regulating AM activation and lung immune responses, we found that AMs are highly susceptible to necroptosis, a form of ICD. Treatment with pan-caspase inhibitors, such as emricasan or benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (ZVAD-fmk), directly induced cell death in AMs, resulting in the release of interleukin (IL)-1α in the lungs. This phenomenon was not observed in mouse lung fibroblasts or bone marrow-derived macrophages, indicating a cell type-specific sensitivity. The process was mediated by receptor-interacting protein kinase (RIPK)1 and RIPK3, and notably occurred without any additional necroptosis triggers such as tumor necrosis factor (TNF) or second mitochondria-derived activator of caspase (SMAC) mimetics. Moreover, activation of the RIPK1-RIPK3 signaling pathway not only triggered necroptosis but also promoted IL-1α production and release. These responses were absent in AMs lacking functional RIPK1 kinase activity or deficient in RIPK3. Importantly, RIPK1/RIPK3-mediated cell death and IL-1α release were sufficient to trigger lung immune responses, as shown by increased antigen-specific IgG and IgA production, which was significantly decreased in mice deficient in necroptosis or lacking the IL-1 receptor. Taken together, these findings demonstrate that the pan-caspase inhibitor emricasan induces necroptotic cell death in AMs and may act as a promising AM-targeted adjuvant to enhance lung-specific acquired immunity.
    DOI:  https://doi.org/10.1038/s41419-025-08372-8
  2. Cell Rep. 2025 Dec 19. pii: S2211-1247(25)01437-8. [Epub ahead of print] 116665
    A TAK1 cytokine toxicity checkpoint controls anti-cancer immunity.
    Tirta M Djajawi, Anne Huber, Sarahi Mendoza Rivera, Akash Srivaths, Maede Salehi, Gokhan Gunay, Chloe Gerak, Liam Neil, Oliver Ozaydin, Olivia Voulgaris, Aleen Al Halawani, Dáire Gannon, Nooshin Khoshdoozmasouleh, Laura J Jenkins, Kok Fei Chan, Andreas Behren, Matthias Ernst, Lisa A Mielke, Emily J Lelliott, Hao Dong, Rebecca Feltham, Vivien R Sutton, Joseph A Trapani, John M Mariadason, Bhupinder Pal, Seamus J Martin, Stephin J Vervoort, Conor J Kearney.
      Cancer immunotherapies benefit only a subset of patients, highlighting the need to define tumor-intrinsic mechanisms of immune evasion. Using a kinome-wide CRISPR-Cas9 screen, we identify MAP3K7 (transforming growth factor beta-activated kinase 1 [TAK1]) as a checkpoint that protects cancer cells from CD8+ T cell-mediated killing. TAK1 integrates tumor necrosis factor (TNF) and interferon gamma (IFNγ) signals to drive a cytoprotective response that blocks cytokine-induced death and prevents bystander killing by perforin-deficient T cells. Inhibition of TAK1 redirects TNF/IFNγ signaling toward apoptosis via RIPK1 and caspase-8 while simultaneously amplifying IFNγ outputs to further prime cells for cytokine-driven death. Mechanistically, TAK1 loss triggers proteasomal degradation of cFLIP, promoting complex II formation and undermining protective pathways. In immune-competent mice, TAK1 deficiency markedly impairs tumor growth, whereas immune-deficient hosts show little effect. Adoptive T cell therapy preferentially eliminates TAK1-deficient clones. These findings establish TAK1 as a tumor-intrinsic immune checkpoint and support TAK1 inhibition as a strategy to enhance cancer immunotherapy.
    Keywords:  CP: cancer; CP: immunology; CRISPR; TAK1; TNF; cFLIP; immunotherapy; interferon gamma
    DOI:  https://doi.org/10.1016/j.celrep.2025.116665
  3. Nat Commun. 2025 Dec 23.
    Decoding necrosome assembly: harmonizing signal amplification and attenuation through optimal RIP3 stoichiometry.
    Xiang Li, Yating Cao, Fei Xu, Yiting Zhang, Yue Kong, Chengjie Lan, Rongfeng Zhu, Cheng Lin, Chuan-Qi Zhong, Zhilong Liu, Hong Qi, Yichuan Huang, Yunshan Xiao, Gui-Quan Sun, Jianwei Shuai, Xin Chen.
      Necrosome assembly is essential for necroptosis, a process implicated in neurodegeneration, ischemic injury, and inflammatory diseases. Yet the spatiotemporal rules governing this assembly remain elusive. Leveraging quantitative STORM and mathematical modeling, we define an approximately 3:1 ratio of RIP3 to RIP1 in necrosomes as the optimal stoichiometry for necroptosis, enabling signal amplification and a threshold response. Surprisingly, excessive RIP3 oligomerization attenuates signaling, acting as an intrinsic size control mechanism. RIP3 assembly is dynamically regulated: it is constrained by stimulation and RIP1, promoted by RIP3 itself, and unexpectedly limited by downstream MLKL. A complementary balance between necrosome quantity and RIP3 assembly degree ensures efficient MLKL phosphorylation. In contrast, Caspase-8 assembly is limited by c-FLIP and recruited linearly by RIP1, while its distinct behavior from RIP3 underlies the biphasic necroptotic response to RIP1. These findings uncover the flexible, multi-strategic nature of signalosomes and offer valuable insights for therapeutic and synthetic biology.
    DOI:  https://doi.org/10.1038/s41467-025-67098-5
  4. Front Cell Dev Biol. 2025 ;13 1699698
    pH-regulated nuclear F-actin assembly during ferroptosis.
    Menghao Qiao, Zhipeng Yan, Jiewei Huang, Yu Fang, Kun Xu, Lingbo Cao, Haiying Mai, Na Li, Yanmei Li, Yunmiao Guo, Junqi Huang.
       Introduction: Ferroptosis is an iron-dependent form of programmed cell death driven by lipid peroxidation and loss of membrane integrity, frequently modeled with small molecules such as RSL3 that inhibit Glutathione Peroxidase 4 (GPX4). Filamentous actin (F-actin) exists within the nucleus, modulating transcription, nuclear mechanics, and chromatin organization, yet its behavior during ferroptosis remain unexplored.
    Methods: Here, we show that nuclear F-actin assembles in HT-1080 cells undergoing RSL3-induced ferroptosis, visualized by phalloidin, SiR-actin, anti-Actin staining, and live 3D/time-lapse imaging of a nuclear actin chromobody (nAC-TagGFP2).
    Results: Mechanistically, nuclear G-actin increased during ferroptosis, and Importin-9 (IPO9) knockdown markedly reduced nuclear F-actin, indicating an import-dependent mechanism. Concurrently, cytoplasmic F-actin underwent substantial remodeling. Overexpression of a polymerization-defective cytoplasmic β-actin mutant (R62D) slightly delayed ferroptosis, whereas nuclear-targeted mutants had no effect, suggesting nuclear F-actin is a concomitant, not causative, feature. Notably, extracellular NaHCO3 or NaOH suppressed nuclear F-actin formation, while a pH-sensitive reporter revealed progressive intracellular acidification during ferroptosis, favoring nuclear F-actin assembly.
    Discussion: These findings reveal nuclear F-actin assembly driven by cytoplasmic actin remodeling, nuclear import, and intracellular acidification, uncovering a previously unrecognized feature of ferroptotic cell death.
    Keywords:  actin; cytoskeleton; ferroptosis; nuclear actin; pH
    DOI:  https://doi.org/10.3389/fcell.2025.1699698
  5. bioRxiv. 2025 Dec 18. pii: 2025.12.17.694518. [Epub ahead of print]
    Primate-specific adaptation of Ku protects transcriptomic integrity by suppressing Alu-mediated alternative splicing.
    Tianji Yu, Jimin Yoon, Yimeng Zhu, Angelina Li, Brian J Lee, Daniel F Moakley, Jing Duan, Qiannian Deng, Fanjia Hou, Mengfang Yan, Vincenzo A Gennarino, Ke Zhang, Li Chen, Shan Zha, Chaolin Zhang.
      Accurate pre-mRNA splicing is essential for the transfer of genetic information but faces unique challenge in higher primates due to the massive expansion of intronic Alu elements 1-3 . While studying Ku, the Ku70/Ku80 heterodimer best known for initiating non-homologous end-joining (NHEJ) by encircling DNA ends 4 , we discovered that Ku expression increased markedly during primate evolution in parallel with Alu expansion 5 . Ku binds double-stranded RNA (dsRNA) stem-loops, including those at the antisense Alu (asAlu) elements within introns 5 . Here, we show that Ku-depletion in human cells has a broad impact on splicing largely independent of cell-cycle states, NHEJ, or innate immune signaling, significantly affecting ~8-10% of quantifiable alternative splicing events. Mechanistically, Ku directly binds exonic asAlu to prevent their aberrant inclusion and binds asAlu within inverted-repeat Alu (irAlu) pairs flanking canonical exons to prevent exon skipping 6 . Among human tissues, Ku expression in the brain is consistently ~50% lower, correlating with more permissive expression of Alu-derived splice variants, particularly those encoding mitochondrial proteins and RNA-binding factors. Correspondingly, heterozygous Ku loss in patient causes developmental delay, neurological dysfunction, and acidosis. Together our findings identified Ku as a critical suppressor of Alu-associated alternative splicing co-opted during evolution with implications for primate brain function and human disease.
    DOI:  https://doi.org/10.64898/2025.12.17.694518
  6. Exp Mol Med. 2025 Dec 26.
    Optogenetic engineering of BAX to control mitochondrial permeabilization and attenuate apoptosis in cells.
    Dain Lee, Hyunjun Bae, Dongwoo Oh, Minseop Kim, Ju-Hee Kim, Jinchul Ahn, Seok-Hyeon Kang, Seo-Hee You, Dong-Hwee Kim, Hyun Jeong Oh, Won Do Heo, Seok Chung.
      Although considerable research has focused on enhancing the apoptotic function of BAX for several decades, inhibition of its functionality remains relatively underexplored, despite intensive BAX activation occurring in various neurodegenerative diseases. Here we present a protein engineering approach to modulate BAX integration into the mitochondrial outer membrane, establishing a tunable strategy for antiapoptosis. Utilizing optogenetic methods that employ cryptochrome 2 and its binding partner cryptochrome-interacting basic helix loop helix 1, we achieved precise spatial control over BAX localization, a critical determinant of its function. Our results demonstrate that the engineered BAX variant is effectively incapacitated in its apoptotic function while also modulating endogenous BAX activity to enhance cellular resistance to apoptosis. These findings not only advance our understanding of BAX regulation but also offer promising prospects for the development of therapeutic strategies against apoptosis-related diseases.
    DOI:  https://doi.org/10.1038/s12276-025-01605-y
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