Fischer Julia, Rusyn Lisa, Krus Frederike, Lobastova Liudmila, Herb Marc, Gluschko Alexander, Hejazi Zahra, Hos Nina J, Calabrese Chiara, Stemler Jannik, Mayer Petra, Hanssen Ruth, Theobald Sebastian, Vehreschild Jörg Janne, Trebicka Jonel, Krönke Martin, Fries Jochen W U, Lehmann Clara, Nguyen Phuong-Hien, Rybniker Jan, Robinson Nirmal, Seeger-Nukpezah Tamina
University of Cologne, Faculty of Medicine and University Hospital of Cologne, Department I of Internal Medicine, Center for Integrated Oncology, Cologne, Germany.
University of Cologne, Faculty of Medicine and University Hospital of Cologne, Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
Cell Death Dis. 2025 Jun 12;16(1):445. doi: 10.1038/s41419-025-07634-9.
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 Macrophages downregulate NEDD9 to counteract ST mediated FAK-AKT activation. Upon infection with ST NEDD9 is translocated from the cytosol to ST-containing phagosomes. Loss of NEDD9 results in enhanced lysosomal capacities supporting bacterial clearance. Strikingly, ST recruits and activates FAK and AKT to suppress endosome-lysosome fusion, thereby bypassing lysosome-mediated pathogen clearance. Created in BioRender. Robinson, N. (2021) BioRender.com/n17r483.
支架蛋白NEDD9通过与粘着斑激酶（FAK）相互作用来协调整合素下游的信号传导，从而促进细胞迁移。NEDD9的表达在许多临床病症（如癌症）中会发生改变，但其在针对感染的固有免疫中的作用仍不清楚。鼠伤寒沙门氏菌（ST）感染的小鼠巨噬细胞的转录组分析显示NEDD9及其信号网络中的基因表达下调。细菌感染诱导宿主介导的巨噬细胞和从血流感染患者分离的外周血单核细胞（PBMC）中NEDD9的溶酶体降解。然而，ST诱导NEDD9从细胞质转运至含有ST的吞噬体，并通过FAK/AKT激活阻止其吞噬溶酶体介导的清除，这反映了一种细菌逃避机制。NEDD9的完全缺失显著降低了ST感染后体外和体内的细菌负荷并增强了炎症。从机制上讲，我们表明NEDD9激活FAK-AKT途径，使FAK和AKT磷酸化，从而损害吞噬溶酶体介导的细菌清除。因此，我们的研究确定NEDD9是巨噬细胞溶酶体功能的关键调节因子，也是治疗细菌感染的潜在宿主导向治疗靶点。分类：生物科学，微生物学巨噬细胞下调NEDD9以对抗ST介导的FAK-AKT激活。感染ST后，NEDD9从细胞质转运至含有ST的吞噬体。NEDD9的缺失导致支持细菌清除的溶酶体能力增强。引人注目的是，ST招募并激活FAK和AKT以抑制内体-溶酶体融合，从而绕过溶酶体介导的病原体清除。由BioRender创建。罗宾逊，N.（2021年）BioRender.com/n17r483 。
