bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2025–07–20
fourteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. Cleavage of the Hippo kinases and programmed cell death in murine macrophages exposed to sterile stimuli and bacterial pathogens.
  2. Endolysosomal damage surveillance enables rapid inflammasome sensing of pathogens.
  3. Acidosis Licenses the NLRP3 Inflammasome-Inhibiting Effects of Beta-Hydroxybutyrate and Short-Chain Carboxylic Acids.
  4. TH5487 specifically targets NLRP3 in FCAS patients resistant to MCC950.
  5. Inactivation of PI3K-C2α deregulates cell death pathways and sensitizes to endotoxic shock.
  6. Cardiolipin inhibits the non-canonical inflammasome by preventing LPS binding to caspase-4/11.
  7. Cell Death, Compensatory Proliferation, and Cell Competition.
  8. A bacterial CARD-NLR immune system controls the release of gene transfer agents.
  9. BRD4 acts as a pH sensor to tune inflammation.
  10. MYD88 mutations in clonal hematopoiesis promote inflammation and hematopoietic stem cell expansion.
  11. Structural modeling reveals viral proteins that manipulate host immune signaling.
  12. A Non-canonical Role for Hepatocyte MLKL in Promoting Mitochondrial Dysfunction and Senescence in the Aging Liver.
  13. Neutrophils drive vascular occlusion, tumour necrosis and metastasis.
  14. ADAM Sheddase Activity Promotes the Detachment of Small Extracellular Vesicles From the Plasma Membrane.
  1. bioRxiv. 2025 Jun 15. pii: 2025.06.15.659776. [Epub ahead of print]
    Cleavage of the Hippo kinases and programmed cell death in murine macrophages exposed to sterile stimuli and bacterial pathogens.
    Sydney M Quagliato, Ryan Mirhosiny, Lucas Meints, Matthew Gulker, Brendyn M St Louis, Yu-Ting Su, Pei-Chung Lee.
      Mammalian STE20-like kinases MST1 and MST2 are the conserved Hippo kinases known for their importance in organ development and tumor suppression. Notably, humans and mice lacking these kinases have increased susceptibility to infection, indicating a role of MST1/2 in immunity. In macrophages that play a critical role in host immunity, MST1/2 are proteolytically cleaved to coordinate different forms of programmed cell death, including apoptosis and pyroptosis. This cleavage event occurs when the innate immune sensors, inflammasomes, are activated by the bacterial pathogen, Legionella pneumophila, or damage-associated molecular patterns. In this report, we determine MST1/2 cleavage in macrophages under various inflammatory conditions and challenges with pathogenic bacteria. The sterile molecules ATP and nigericin induce MST1/2 cleavage and apoptosis when the NLRP3 inflammasome and GSDMD-mediated pyroptosis are activated. Remarkably, in conditions without NLRP3 or GSDMD activation, MST1/2 are still cleaved by caspases to promote cell death in macrophages treated with these sterile molecules. During infection, wildtype macrophages trigger MST1/2 cleavage and apoptosis against L. pneumophila and Yersinia pseudotuberculosis but preferentially activate GSDMD-mediated pyroptosis against Pseudomonas aeruginosa and Salmonella enterica Typhimurium. Interestingly, GSDMD knockout macrophages opt to cleave MST1/2 and undergo apoptosis in response to P. aeruginosa and S. enterica , suggesting an interplay between GSDMD and MST1/2. Together, macrophages funnel apoptotic death signals through MST1/2 cleavage upon stimulation of the inflammatory molecules and pathogens, which illustrates the broad implications of the host Hippo kinases in infections and sterile inflammation.
    DOI:  https://doi.org/10.1101/2025.06.15.659776
  2. Cell Rep. 2025 Jul 15. pii: S2211-1247(25)00773-9. [Epub ahead of print]44(8): 116002
    Endolysosomal damage surveillance enables rapid inflammasome sensing of pathogens.
    Sonia Shivcharan, Doulathunnisa Ahamed Younis, Skylar S Wright, Chengliang Wang, Bharat Behl, Patience Shumba, Kristina N Delgado, Arshmeet K Chawla, Neal M Alto, Noorjahan Panjwani, Sivapriya Kailasan Vanaja, Jianbin Ruan, Zhichao Fan, Vijay A Rathinam.
      Host cell cytosol is monitored by inflammasomes. Cytosolic invasion of pathogens involves breaching endolysosomal membranes, which is sensed by galectins triggering endolysosomal damage response. Whether and how endomembrane damage surveillance impacts inflammasome sensing of pathogens is unknown. Here, we show that endosomal damage sensing by galectin-8 licenses rapid noncanonical inflammasome sensing of intracellular bacteria; caspase-4 sensing of cytosol-invading bacteria, the consequent gasdermin D (GSDMD)-mediated pyroptosis, and interleukin (IL)-18 activation are greatly reduced in galectin-8-deficient human epithelial cells. Interestingly, galectin-8 promotes caspase-4 activation independently of the autophagic receptor NDP52 and bacterial restriction. Instead, we demonstrate that galectin-8 exists in a complex with caspase-4 in naive cells and recruits caspase-4 to bacteria upon endolysosomal rupture, enabling lipopolysaccharide (LPS) sensing. Collectively, this study reveals galectin-8 as a hub integrating endomembrane damage sensing and inflammasome sensing. Thus, tethering the pathogen sensor caspase-4 to the endomembrane damage sensor galectin-8 poises the host to rapidly detect bacteria that breach the endolysosomal network.
    Keywords:  CP: Immunology; caspase-4; cell death; endolysosomes; galectins; gasdermin D; inflammasome; pathogen sensing; pyroptosis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116002
  3. bioRxiv. 2025 May 07. pii: 2025.05.01.650510. [Epub ahead of print]
    Acidosis Licenses the NLRP3 Inflammasome-Inhibiting Effects of Beta-Hydroxybutyrate and Short-Chain Carboxylic Acids.
    Madeleine M Mank, Kaitlyn A Zoller, V Amanda Fastiggi, Jennifer L Ather, Matthew E Poynter.
      NLRP3 inflammasome activation induces the cleavage and secretion of IL-1β and IL-18, and causes pyroptosis. Generated during times of energetic crisis ( e.g. , caloric insufficiency), the ketone body β-hydroxybutyrate (BHB) has been reported to inhibit NLRP3 inflammasome activation. However, the conditions under which BHB exerts this activity and whether other short-chain carboxylic acids (SCCAs) share this effect are unexplored. Since BHB is often produced in high abundance endogenously accompanied by metabolic acidosis, we aimed to examine the pH-dependence for the ability of BHB and similar molecules to inhibit NLRP3 inflammasome activation and to test receptors conferring these effects. Whereas β-hydroxybutyric acid (BHBA) enantiomers function equivalently to dose-dependently inhibit NLRP3 inflammasome-induced IL-1β secretion, sodium-β-hydroxybutyrate (NaBHB) and NaOH-neutralized BHBA do not inhibit NLRP3 inflammasome activation. Acidifying the pH of the NaBHB stock solution or the media in which cells are exposed to NaBHB, or allowing the cells to endogenously acidify their media, enables NaBHB to inhibit NLRP3 inflammasome activation. Several other SCCAs also inhibit NLRP3 inflammasome activation in a pH-dependent manner and prevent pyroptotic cell death. Finally, Free Fatty Acid Receptor 3 (GPR41/FFAR3) activation phenocopies and augments the NLRP3 inflammasome-inhibiting effects of BHBA. In conclusion, acidification licenses the ability of BHB and related SCCAs to inhibit NLRP3 inflammasome activation, in part through GPR41/FFAR3, thereby expanding the repertoire of metabolites capable of modulating this important pro-inflammatory pathway during times of energetic crisis and optimizing conditions for the potential use of ketone bodies as anti-inflammatories.
    DOI:  https://doi.org/10.1101/2025.05.01.650510
  4. bioRxiv. 2025 Jun 08. pii: 2025.06.05.658156. [Epub ahead of print]
    TH5487 specifically targets NLRP3 in FCAS patients resistant to MCC950.
    Angela Lackner, Lemuel Leonidas, Alijah Macapagal, Hannah Lee, Huilin Xu, Yanfei Qiu, Melissa Campos, Julia E Cabral, Janset Onyuru, Sanika Kulkarni, Lauren V Albrecht, Hal M Hoffman, Reginald McNulty.
      The NLRP3 inflammasome plays a central role in innate immunity and is activated in response to mitochondrial dysfunction and oxidized DNA. Here, we demonstrate that repurposed small-molecule inhibitors originally developed for DNA glycosylases, TH5487 and SU0268, potently inhibit NLRP3 activation ex vivo in human Peripheral Blood Mononuclear Cells (PBMCs) with IC 50 of 1.62 µM and 3.24 µM, respectively. We show that these inhibitors prevent mitochondrial localization of NLRP3 and directly block inflammasome assembly. They also reshape the immune landscape decreasing IL-1β, while increasing IFN-β. Structural and biophysical analyses reveal a two-site DNA binding model in which NLRP3 engages oxidized DNA with a KD1 of 0.268 nM and KD2 3.02 nM. Importantly, these inhibitors block IL-1β secretion in L353P Familial Cold Autoinflammatory Syndrome (FCAS) patient PBMCs where MCC950 fails, demonstrating the therapeutic potential for inflammasome-driven diseases. Together, our findings reveal a novel druggable mechanism of inflammasome inhibition through interference with oxidized DNA sensing and localization, offering new opportunities for treatment of chronic inflammatory disorders.
    DOI:  https://doi.org/10.1101/2025.06.05.658156
  5. Proc Natl Acad Sci U S A. 2025 Jul 22. 122(29): e2423358122
    Inactivation of PI3K-C2α deregulates cell death pathways and sensitizes to endotoxic shock.
    York Posor, Sarah E Conduit, Wayne Pearce, Daniele Morelli, Georgia Constantinou, Maria Whitehead, Neil J Sebire, Cheryl L Scudamore, Nieves Peltzer, Henning Walczak, Bart Vanhaesebroeck.
      The organismal roles of the class II PI3K isoform PI3K-C2α remain poorly understood. Recent studies have found PI3K-C2α to promote arterial thrombosis and breast cancer metastasis, generating interest in this kinase as a drug target, with small molecule PI3K-C2α inhibitors now available. However, the consequences of systemic PI3K-C2α inactivation in the nondiseased, postnatal state are largely unknown. Here, we show that induction of genetic PI3K-C2α inactivation in adult mice is well tolerated, without adverse effects on normal physiology. Surprisingly, however, mice with inactive PI3K-C2α display strong sensitization to challenge with bacterial lipopolysaccharide (LPS), a model of endotoxic shock. This sensitization is recapitulated by vascular endothelial-specific deletion of PI3K-C2α. Furthermore, sensitization to LPS can be fully rescued by disabling extrinsic induction of cell death by combined caspase-8- and RIPK3 deficiency. These observations validate the tolerability of systemic PI3K-C2α inhibition in principle but reveal an unexpected role for PI3K-C2α in the regulation of extrinsic cell death pathways.
    Keywords:  PI3K; endotoxic shock; phosphoinositide; regulated cell death; vascular endothelia
    DOI:  https://doi.org/10.1073/pnas.2423358122
  6. EMBO J. 2025 Jul 16.
    Cardiolipin inhibits the non-canonical inflammasome by preventing LPS binding to caspase-4/11.
    Malvina Pizzuto, Mercedes Monteleone, Sabrina Sofia Burgener, Jakub Began, Melan Kurera, Jing Rong Chia, Emmanuelle Frampton, Joanna Crawford, Monalisa Oliveira, Kirsten M Kenney, Jared R Coombs, Masahiro Yamamoto, Si Ming Man, Petr Broz, Pablo Pelegrin, Kate Schroder.
      Caspase-4 and caspase-11 (CASP4/11) sense bacterial lipopolysaccharide (LPS). Currently available inhibitors of CASP4/11 also block the activity of caspase-1 (CASP1), which restricts their usefulness in the study of CASP4/11 functions, as well as their clinical potential for the treatment of LPS-linked diseases through CASP4/11 inhibition. Here, we identify mitochondrial cardiolipin as a selective inhibitor of CASP4/11-dependent cell death and inflammatory cytokine secretion, without affecting CASP1 function. Cardiolipin targets the CARD domain of CASP4/11, impeding its interaction with LPS to restrain CASP4/11 activation, thereby suppressing LPS-induced systemic inflammation in vivo. By identifying cardiolipin as a selective inhibitor of CASP4/11, we provide an urgently needed tool for studying caspase-4/11 and noncanonical inflammasome functions in inflammatory pathways and LPS-induced pathogenesis.
    Keywords:  Cardiolipin; Caspase-11; Caspase-4; LPS; Noncanonical Inflammasome
    DOI:  https://doi.org/10.1038/s44318-025-00507-z
  7. Annu Rev Genet. 2025 Jul 17.
    Cell Death, Compensatory Proliferation, and Cell Competition.
    Andreas Bergmann.
      Cell death, compensatory proliferation, and cell competition are fundamental interconnected processes that shape how tissues develop, maintain homeostasis, and regenerate. In this review, I highlight how cell death (apoptosis) not only eliminates excess and damaged cells but can also initiate compensatory proliferation, an adaptive response that occurs following cell loss. I examine cell competition, a quality-control mechanism that removes less fit loser cells in favor of healthier winner neighbors. Cell competition is intricately linked to cell death and compensatory proliferation. I present the history of these processes, discuss the most important examples, and reveal the key molecular mechanisms that underlie them. I incorporate findings from Caenorhabditis elegans, Drosophila melanogaster, vertebrates, and other models to underscore the conservation of the key molecular signaling events. I also discuss how misregulation of these processes can contribute to pathological conditions, including cancer.
    DOI:  https://doi.org/10.1146/annurev-genet-012125-083359
  8. bioRxiv. 2025 May 08. pii: 2025.05.08.652646. [Epub ahead of print]
    A bacterial CARD-NLR immune system controls the release of gene transfer agents.
    Emma J Banks, Pavol Bardy, Ngat T Tran, Phuong M Nguyen, Abbas Maqbool, Tung B K Le.
      Bacteria have evolved a wide array of immune systems to detect and defend against external threats including mobile genetic elements (MGEs) such as bacteriophages, plasmids, and transposons. MGEs are often selfish, exploiting their bacterial hosts to propagate, however they can also provide adaptive advantages through horizontal gene transfer. Gene transfer agents (GTAs), which are non-infectious domesticated prophages, represent a unique class of beneficial MGEs that facilitate bacterial gene transfer. Despite their domestication, GTAs retain phage-like features, including the requirement for host cell lysis to release particles, that may inadvertently trigger host immunity. How GTAs might avoid, subvert, or possibly adopt host immune systems to complete their life stages is poorly understood. Here, we identify a tripartite system, LypABC, that is essential for GTA-mediated cell lysis in Caulobacter crescentus. LypABC resembles caspase recruitment domain-nucleotide-binding leucine-rich repeat (CARD-NLR) anti-phage defence systems that mediate abortive infection wherein infected cells die to prevent phage proliferation, thereby protecting the overall bacterial population. LypABC-deficient cells produce host DNA-packed GTA particles and eventually die but cannot lyse to release GTA particles. Moreover, overproduction of LypABC is highly toxic to both GTA-producing and non-producing cells, highlighting the need for strict regulation. We find that such regulation is achieved transcriptionally by a repressor, RogB, which binds the promoters of lypABC and of essential GTA activator genes, thus coupling GTA activation and host cell lysis. While traditionally considered antagonistic towards MGEs, our findings here suggest that immunity components are versatile and can be adapted to support MGEs.
    DOI:  https://doi.org/10.1101/2025.05.08.652646
  9. Nat Rev Immunol. 2025 Jul 17.
    BRD4 acts as a pH sensor to tune inflammation.
    Siu Ling Tai, Arthur Mortha.
      
    DOI:  https://doi.org/10.1038/s41577-025-01213-x
  10. bioRxiv. 2025 Jun 25. pii: 2025.06.19.660202. [Epub ahead of print]
    MYD88 mutations in clonal hematopoiesis promote inflammation and hematopoietic stem cell expansion.
    Jennifer Yeung, Sophia Y Philbrook, Emma Uible, Lynn Lee, Kwangmin Choi, Puneet Agarwal, Courtnee A Clough, Pravin Patel, Kathryn A Wikenheiser-Brokamp, Kathleen Hueneman, Hans Christian Reinhardt, Tzyy-Jye Doong, Arletta Lozanski, Gerard Lozanski, Tamanna Haque, Erin Hertlein, John C Byrd, Daniel T Starczynowski.
      Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by expansion of mutant hematopoietic stem and progenitor cells (HSPCs) and an increased risk of chronic diseases and cancers. While mutations in DNMT3A , TET2 , and ASXL1 are common in CHIP, the contribution of less frequent gene mutations is not well understood. Here, we report MYD88 mutations, including lymphoma-associated and novel variants in blood cells of the general population and newly diagnosed solid cancer patients. MYD88 CHIP mutations in HSPCs activate NF-κB, indicating a gain-of-function activity. Modeling MYD88 CHIP in mice, Myd88 L252P (equivalent of human L265P) expression resulted in a competitive fitness advantage of HSPCs. Myd88 L252P HSPCs exhibit a myeloid cell bias and inflammation, leading to hematologic disease. Single-cell RNA sequencing indicated that Myd88 L252P expands distinct hematopoietic and immune cell clusters and activates immune-related pathways in HSPCs. An IRAK1/4 inhibitor suppressed MYD88-dependent NF-κB activation and reversed Myd88 L252P cell expansion. Overall, MYD88 mutations contribute to CHIP by inducing innate immune pathways in HSPCs and inflammatory disease.
    DOI:  https://doi.org/10.1101/2025.06.19.660202
  11. bioRxiv. 2025 Jul 12. pii: 2025.07.12.664507. [Epub ahead of print]
    Structural modeling reveals viral proteins that manipulate host immune signaling.
    Nitzan Tal, Romi Hadari, Renee B Chang, Ilya Osterman, Roy Jacobson, Erez Yirmiya, Nathalie Bechon, Dina Hochhauser, Miguel López Rivera, Barak Madhala, Jeremy Garb, Tanita Wein, Philip Kranzusch, Gil Amitai, Rotem Sorek.
      Immune pathways that use intracellular nucleotide signaling are common in animals, plants and bacteria. Viruses can inhibit nucleotide immune signaling by producing proteins that sequester or cleave the immune signals. Here we analyzed evolutionarily unrelated signal-sequestering viral proteins, finding that they share structural and biophysical traits in their genetic organization, ternary structures and binding pocket properties. Based on these traits we developed a structure-guided computational pipeline that can sift through large phage genome databases to unbiasedly predict phage proteins that manipulate bacterial immune signaling. Numerous previously uncharacterized proteins, grouped into three families, were verified to inhibit the bacterial Thoeris and CBASS signaling systems. Proteins of the Sequestin and Lockin families bind and sequester the TIR-produced signaling molecules 3'cADPR and His-ADPR, while proteins of the Acb5 family cleave and inactivate 3'3'-cGAMP and related molecules. X-ray crystallography and structural modeling, combined with mutational analyses, explain the structural basis for sequestration or cleavage of the immune signals. Thousands of these signal-manipulating proteins were detected in phage protein databases, with some instances present in well-studied model phages such as T2, T4 and T6. Our study explains how phages commonly evade bacterial immune signaling, and offers a structure-guided analytical approach for discovery of viral immune-manipulating proteins in any database of choice.
    DOI:  https://doi.org/10.1101/2025.07.12.664507
  12. bioRxiv. 2025 May 03. pii: 2025.05.02.651782. [Epub ahead of print]
    A Non-canonical Role for Hepatocyte MLKL in Promoting Mitochondrial Dysfunction and Senescence in the Aging Liver.
    Sabira Mohammed, Chao Jiang, Travis Pennington, Shylesh Bhaskaran, Phoebe Ohene-Marfo, Constantin Georgescu, Kamille Pitts, Albert Tran, Zongkai Peng, Amit Singh, Zhibo Yang, Tiangang Li, Bethany Hannafon, Courtney Houchen, Jonathan D Wren, Veronica Galvan, Nagib Ahsan, Michael Kinter, Tommy L Lewis, Sathyaseelan S Deepa.
      Liver aging is characterized by chronic inflammation and metabolic dysfunction that contributes to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Necroptosis, a form of inflammatory cell death, is activated in aging livers, and genetic ( Ripk3 -/- or Mlkl -/- mice) or pharmacological (RIPK1 inhibitor necrostatin-1s) inhibition of necroptosis attenuates liver inflammation and pathology. However, the cell type-specific role of necroptosis in liver aging remains unclear. Given that MLKL is expressed in hepatocytes, and its expression increases with age, we generated hepatocyte-specific MLKL-overexpressing mice (MLKL HepOE ) to determine its role in liver aging. Unexpectedly, MLKL overexpression in hepatocytes did not induce necroptosis, but instead upregulated markers of cellular senescence (cell cycle arrest genes and SASP factors), increased macrophage infiltration, and elevated M1 macrophage marker expression. Electron microscopy and mitochondrial analyses revealed abnormal mitochondrial morphology, elevated oxidative stress, and disrupted mitochondrial dynamics, while lipidomics demonstrated alterations in hepatic lipid metabolites. In agreement with our observations in MLKL HepOE mice, MLKL overexpression in AML12 hepatocytes impaired mitochondrial respiration, increased proinflammatory extracellular vesicle (EV) release, and induced senescence markers, without triggering cell death. Together, these findings reveal a non-lethal, non-necroptotic role for MLKL in promoting hepatocyte senescence and metabolic dysfunction via mitochondrial impairment and EV-mediated inflammation. Our study highlights MLKL as a novel driver of liver inflammaging and a potential therapeutic target for age-related liver disease.
    DOI:  https://doi.org/10.1101/2025.05.02.651782
  13. Nature. 2025 Jul 16.
    Neutrophils drive vascular occlusion, tumour necrosis and metastasis.
    Jose M Adrover, Xiao Han, Lijuan Sun, Takeo Fujii, Nicole Sivetz, Juliane Daßler-Plenker, Clary Evans, Jessica Peters, Xue-Yan He, Courtney D Cannon, Won Jin Ho, George Raptis, R Scott Powers, Mikala Egeblad.
      Tumour necrosis is associated with poor prognosis in cancer1,2 and is thought to occur passively when tumour growth outpaces nutrient supply. Here we report, however, that neutrophils actively induce tumour necrosis. In multiple cancer mouse models, we found a tumour-elicited Ly6GHighLy6CLow neutrophil population that was unable to extravasate in response to inflammatory challenges but formed neutrophil extracellular traps (NETs) more efficiently than classical Ly6GHighLy6CHigh neutrophils. The presence of these 'vascular-restricted' neutrophils correlated with the appearance of a 'pleomorphic' necrotic architecture in mice. In tumours with pleomorphic necrosis, we found intravascular aggregates of neutrophils and NETs that caused occlusion of the tumour vasculature, driving hypoxia and necrosis of downstream vascular beds. Furthermore, we found that cancer cells adjacent to these necrotic regions (that is, in 'perinecrotic' areas) underwent epithelial-to-mesenchymal transition, explaining the paradoxical metastasis-enhancing effect of tumour necrosis. Blocking NET formation genetically or pharmacologically reduced the extent of tumour necrosis and lung metastasis. Thus, by showing that NETs drive vascular occlusion, pleomorphic necrosis and metastasis, we demonstrate that tumour necrosis is not necessarily a passive byproduct of tumour growth and that it can be blocked to reduce metastatic spread.
    DOI:  https://doi.org/10.1038/s41586-025-09278-3
  14. J Extracell Vesicles. 2025 Jul;14(7): e70114
    ADAM Sheddase Activity Promotes the Detachment of Small Extracellular Vesicles From the Plasma Membrane.
    Chloé Bizingre, Zaira Arellano-Anaya, Flavien Picard, Mathéa Pietri, Anne Baudry, Florence Roussel, Clara Bianchi, Aurélie Alleaume-Butaux, Hector Ardila-Osorio, Maryse Romao, Grégory Lavieu, Graça Raposo, Benoit Schneider.
      Small extracellular vesicles (SEVs) are involved in diverse functions in normal and pathological situations, including intercellular communication, immunity, metastasis and neurodegeneration. Cell release of SEVs is assumed to occur passively right after multivesicular bodies of the endocytic pathway fuse with the plasma membrane. We show here that the completion of SEV release depends on membrane-bound ADAM10 and ADAM17 sheddases that promote the detachment of SEVs from the cell surface by catalysing the cleavage of adhesion proteins of the SEV membrane. The intensity of ADAM10/17-mediated release of SEVs depends on a balanced control of 3-phosphoinositide-dependent kinase 1 (PDK1) and ERK1/2 signalling pathways converging on 90-kDa ribosomal S6 kinase-2 (RSK2), which, in turn, fine-tunes ADAM17 bioavailability and ADAM10/17 enzymatic activities at the plasma membrane, according to a mechanism that relies, at least in part, on variation of the rhomboid-like pseudoprotease iRhom2 cell surface level. By identifying a new proteolytic step involved in the basal release of SEVs, our work may help understand how the deregulation of ADAM10/17-mediated discharge of SEVs contributes to several pathological states.
    Keywords:  ERK1/2; PDK1; RSK2; exosomes; iRhom2; protein cleavage; signalling
    DOI:  https://doi.org/10.1002/jev2.70114
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