bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2025–08–24
two papers selected by
Kateryna Shkarina, Universität Bonn
  1. The expanding role of the NLRP3 inflammasome from periodic fevers to therapeutic targets.
  2. RNA Pol II inhibition activates cell death independently from the loss of transcription.
  1. Nat Immunol. 2025 Aug 18.
    The expanding role of the NLRP3 inflammasome from periodic fevers to therapeutic targets.
    Alexander N R Weber, Róisín M McManus, Veit Hornung, Matthias Geyer, Jasmin B Kuemmerle-Deschner, Eicke Latz.
      Understanding and treating inflammation has proven a formidable challenge. The initiator and central motor of inflammation, the protein NLRP3, is an innate immune sentinel and nonspecific sensor of cellular perturbation. A wide array of inflammatory triggers prompts the formation of an NLRP3 'inflammasome' complex, leading to inflammatory interleukin-1 family cytokine release and pyroptotic cell death. Since gain-of-function mutations in NLRP3 were demonstrated to cause a rare autoinflammatory disease termed cryopyrin-associated periodic syndrome, NLRP3 has emerged as key mediator of inflammation in mouse models for many common diseases, including atherosclerosis, Alzheimer's disease and gout. But even though small-molecule NLRP3 modulators have entered clinical development, many aspects of NLRP3 activation and regulation in humans remain relatively unclear. This Review summarizes the current understanding of the molecular mechanisms that drive NLRP3 inflammasome activation and regulation, and discusses emerging targeting strategies. Understanding these processes can guide precision medicine approaches aimed at mitigating NLRP3-driven pathologies.
    DOI:  https://doi.org/10.1038/s41590-025-02230-7
  2. Cell. 2025 Aug 14. pii: S0092-8674(25)00856-6. [Epub ahead of print]
    RNA Pol II inhibition activates cell death independently from the loss of transcription.
    Nicholas W Harper, Gavin A Birdsall, Megan E Honeywell, Kelly M Ward, Athma A Pai, Michael J Lee.
      RNA Pol II-mediated transcription is essential for eukaryotic life. Although loss of transcription is thought to be universally lethal, the associated mechanisms promoting cell death are not yet known. Here, we show that death following the loss of RNA Pol II activity does not result from dysregulated gene expression. Instead, it occurs in response to loss of the hypophosphorylated form of Rbp1 (also called RNA Pol IIA). Loss of RNA Pol IIA exclusively activates apoptosis, and expression of a transcriptionally inactive version of Rpb1 rescues cell viability. Using functional genomics, we identify the mechanisms driving lethality following the loss of RNA Pol IIA, which we call the Pol II degradation-dependent apoptotic response (PDAR). Using the genetic dependencies of PDAR, we identify clinically used drugs that owe their lethality to a PDAR-dependent mechanism. Our findings unveil an apoptotic signaling response that contributes to the efficacy of a wide array of anti-cancer therapies.
    Keywords:  BCL2L12; DNA damage; PTBP1; RNA polymerase II; apoptosis; cancer therapy; cell death; chemotherapy; cisplatin; transcription
    DOI:  https://doi.org/10.1016/j.cell.2025.07.034
This page is being maintained by Thomas Krichel. It was last updated on 2025‒08‒24 at 9:14.