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<p>The scaffolding protein NEDD9 coordinates signaling downstream of integrins by interacting with focal adhesion kinase (FAK) and thereby promotes cell migration. NEDD9 expression is altered in a number of clinical conditions such as cancer, but its role in innate immunity against infections remains elusive. Transcriptome analysis of <i>Salmonella</i> Typhimurium (<i>S</i>T)-infected murine macrophages showed downregulation of <i>NEDD9</i> and genes belonging to its signaling network. Bacterial infections induced host-mediated lysosomal degradation of NEDD9 in macrophages and PBMCs isolated from patients suffering from bloodstream infection. However, <i>S</i>T induced translocation of NEDD9 from the cytoplasm to <i>S</i>T-containing phagosomes and prevented their phagolysosome-mediated clearance by FAK/AKT activation, reflecting a bacterial evasion mechanism. Complete loss of NEDD9 significantly reduced bacterial burden and enhanced inflammation upon <i>S</i>T infection both in vitro and in vivo. Mechanistically, we show that NEDD9 activates the FAK-AKT pathway allowing phosphorylation of FAK and AKT to impair phagolysosomal-mediated clearance of bacteria. Our study has thus identified NEDD9 as a critical regulator of lysosomal function in macrophages and a potential host-directed therapeutic target to treat bacterial infections.</p><p><b>Classification:</b> Biological Sciences, Microbiology</p><p></p>

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Macrophages downregulate NEDD9 to counteract S. Typhimurium- mediated FAK-AKT activation and lysosome inhibition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月12日

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  • Julia Fischer,
  • Lisa Rusyn,
  • Frederike Krus,
  • Liudmila Lobastova,
  • Marc Herb,
  • Alexander Gluschko,
  • Zahra Hejazi,
  • Nina J. Hos,
  • Chiara Calabrese,
  • Jannik Stemler,
  • Petra Mayer,
  • Ruth Hanssen,
  • Sebastian J. Theobald,
  • Jörg Janne Vehreschild,
  • Jonel Trebicka,
  • Martin Krönke,
  • Jochen W. U. Fries,
  • Clara Lehmann,
  • Phuong-Hien Nguyen,
  • Jan Rybniker,
  • Nirmal Robinson,
  • Tamina Seeger-Nukpezah

摘要

The scaffolding protein NEDD9 coordinates signaling downstream of integrins by interacting with focal adhesion kinase (FAK) and thereby promotes cell migration. NEDD9 expression is altered in a number of clinical conditions such as cancer, but its role in innate immunity against infections remains elusive. Transcriptome analysis of Salmonella Typhimurium (ST)-infected murine macrophages showed downregulation of NEDD9 and genes belonging to its signaling network. Bacterial infections induced host-mediated lysosomal degradation of NEDD9 in macrophages and PBMCs isolated from patients suffering from bloodstream infection. However, ST induced translocation of NEDD9 from the cytoplasm to ST-containing phagosomes and prevented their phagolysosome-mediated clearance by FAK/AKT activation, reflecting a bacterial evasion mechanism. Complete loss of NEDD9 significantly reduced bacterial burden and enhanced inflammation upon ST infection both in vitro and in vivo. Mechanistically, we show that NEDD9 activates the FAK-AKT pathway allowing phosphorylation of FAK and AKT to impair phagolysosomal-mediated clearance of bacteria. Our study has thus identified NEDD9 as a critical regulator of lysosomal function in macrophages and a potential host-directed therapeutic target to treat bacterial infections.

Classification: Biological Sciences, Microbiology