Universität zu Köln

Fischer, Julia ORCID: 0000-0001-6138-7454, Rusyn, Lisa, Krus, Frederike, Lobastova, Liudmila ORCID: 0009-0007-8600-1547, Herb, Marc ORCID: 0000-0002-7533-0288, Gluschko, Alexander ORCID: 0000-0002-1090-1756, Hejazi, Zahra, Hos, Nina J., Calabrese, Chiara, Stemler, Jannik ORCID: 0000-0001-9152-2469, Mayer, Petra ORCID: 0009-0007-8837-9279, Hanssen, Ruth ORCID: 0000-0002-7283-9302, Theobald, Sebastian J., Vehreschild, Jörg Janne ORCID: 0000-0002-5446-7170, Trebicka, Jonel, Krönke, Martin ORCID: 0000-0003-0566-0692, Fries, Jochen W. U. ORCID: 0000-0003-2054-6345, Lehmann, Clara ORCID: 0000-0002-7042-1578, Nguyen, Phuong-Hien ORCID: 0000-0002-3249-7264, Rybniker, Jan ORCID: 0000-0001-8351-2690, Robinson, Nirmal ORCID: 0000-0002-7361-9491 and Seeger-Nukpezah, Tamina ORCID: 0000-0002-4906-7834 (2025). Macrophages downregulate NEDD9 to counteract S. Typhimurium- mediated FAK-AKT activation and lysosome inhibition. Cell Death & Disease, 16 (1). pp. 1-13. Springer Nature. ISSN 2041-4889

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Abstract

[Artikel-Nr.: 445] 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 ( S T)-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, S T induced translocation of NEDD9 from the cytoplasm to S 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 S 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.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Fischer, Julia UNSPECIFIED https://orcid.org/0000-0001-6138-7454 UNSPECIFIED Rusyn, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Krus, Frederike UNSPECIFIED UNSPECIFIED UNSPECIFIED Lobastova, Liudmila UNSPECIFIED https://orcid.org/0009-0007-8600-1547 UNSPECIFIED Herb, Marc UNSPECIFIED https://orcid.org/0000-0002-7533-0288 UNSPECIFIED Gluschko, Alexander UNSPECIFIED https://orcid.org/0000-0002-1090-1756 UNSPECIFIED Hejazi, Zahra UNSPECIFIED UNSPECIFIED UNSPECIFIED Hos, Nina J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Calabrese, Chiara UNSPECIFIED UNSPECIFIED UNSPECIFIED Stemler, Jannik UNSPECIFIED https://orcid.org/0000-0001-9152-2469 UNSPECIFIED Mayer, Petra UNSPECIFIED https://orcid.org/0009-0007-8837-9279 UNSPECIFIED Hanssen, Ruth UNSPECIFIED https://orcid.org/0000-0002-7283-9302 UNSPECIFIED Theobald, Sebastian J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vehreschild, Jörg Janne UNSPECIFIED https://orcid.org/0000-0002-5446-7170 UNSPECIFIED Trebicka, Jonel UNSPECIFIED UNSPECIFIED UNSPECIFIED Krönke, Martin UNSPECIFIED https://orcid.org/0000-0003-0566-0692 UNSPECIFIED Fries, Jochen W. U. UNSPECIFIED https://orcid.org/0000-0003-2054-6345 UNSPECIFIED Lehmann, Clara UNSPECIFIED https://orcid.org/0000-0002-7042-1578 UNSPECIFIED Nguyen, Phuong-Hien UNSPECIFIED https://orcid.org/0000-0002-3249-7264 UNSPECIFIED Rybniker, Jan UNSPECIFIED https://orcid.org/0000-0001-8351-2690 UNSPECIFIED Robinson, Nirmal UNSPECIFIED https://orcid.org/0000-0002-7361-9491 UNSPECIFIED Seeger-Nukpezah, Tamina UNSPECIFIED https://orcid.org/0000-0002-4906-7834 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-801529
Identification Number:	10.1038/s41419-025-07634-9
Journal or Publication Title:	Cell Death & Disease
Volume:	16
Number:	1
Page Range:	pp. 1-13
Number of Pages:	13
Date:	12 June 2025
Publisher:	Springer Nature
ISSN:	2041-4889
Language:	English
Faculty:	External institution Faculty of Medicine
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing Außeruniversitäre Forschungseinrichtungen > MPI for Metabolism Research CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie Faculty of Medicine > Innere Medizin > Poliklinik für Endokrinologie, Diabetologie und Präventivmedizin Faculty of Medicine > Medizinische Mikrobiologie, Immunologie und Hygiene > Institut für Medizinische Mikrobiologie, Immunologie und Hygiene Faculty of Medicine > Pathologie und Neuropathologie > Institut für Pathologie Zentrum für Molekulare Medizin
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Biological ; Sciences ; Microbiology English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80152