Universität zu Köln

Knopf, Julia D. ORCID: 0000-0002-5344-9771, Steigleder, Susanne S. ORCID: 0009-0001-9322-5916, Korn, Friederike ORCID: 0009-0009-0780-4195, Kühnle, Nathalie, Badenes, Marina ORCID: 0000-0001-6872-891X, Tauber, Marina, Theobald, Sebastian J. ORCID: 0000-0001-7042-8326, Rybniker, Jan ORCID: 0000-0001-8351-2690, Adrain, Colin ORCID: 0000-0001-7597-4393 and Lemberg, Marius K. ORCID: 0000-0002-0996-1268 (2024). RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling. Nature Communications, 15 (1). pp. 1-13. Springer Nature. ISSN 2041-1723

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Abstract

[Artikel-Nr.: 1528] The toll-like receptor 4 (TLR4) is a central regulator of innate immunity that primarily recognizes bacterial lipopolysaccharide cell wall constituents to trigger cytokine secretion. We identify the intramembrane protease RHBDL4 as a negative regulator of TLR4 signaling. We show that RHBDL4 triggers degradation of TLR4’s trafficking factor TMED7. This counteracts TLR4 transport to the cell surface. Notably, TLR4 activation mediates transcriptional upregulation of RHBDL4 thereby inducing a negative feedback loop to reduce TLR4 trafficking to the plasma membrane. This secretory cargo tuning mechanism prevents the over-activation of TLR4-dependent signaling in an in vitro Mycobacterium tuberculosis macrophage infection model and consequently alleviates septic shock in a mouse model. A hypomorphic RHBDL4 mutation linked to Kawasaki syndrome, an ill-defined inflammatory disorder in children, further supports the pathophysiological relevance of our findings. In this work, we identify an RHBDL4-mediated axis that acts as a rheostat to prevent over-activation of the TLR4 pathway.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Knopf, Julia D. UNSPECIFIED https://orcid.org/0000-0002-5344-9771 UNSPECIFIED Steigleder, Susanne S. UNSPECIFIED https://orcid.org/0009-0001-9322-5916 UNSPECIFIED Korn, Friederike UNSPECIFIED https://orcid.org/0009-0009-0780-4195 UNSPECIFIED Kühnle, Nathalie UNSPECIFIED UNSPECIFIED UNSPECIFIED Badenes, Marina UNSPECIFIED https://orcid.org/0000-0001-6872-891X UNSPECIFIED Tauber, Marina UNSPECIFIED UNSPECIFIED UNSPECIFIED Theobald, Sebastian J. UNSPECIFIED https://orcid.org/0000-0001-7042-8326 UNSPECIFIED Rybniker, Jan UNSPECIFIED https://orcid.org/0000-0001-8351-2690 UNSPECIFIED Adrain, Colin UNSPECIFIED https://orcid.org/0000-0001-7597-4393 UNSPECIFIED Lemberg, Marius K. UNSPECIFIED https://orcid.org/0000-0002-0996-1268 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-814540
Identification Number:	10.1038/s41467-024-45615-2
Journal or Publication Title:	Nature Communications
Volume:	15
Number:	1
Page Range:	pp. 1-13
Number of Pages:	13
Date:	7 March 2024
Publisher:	Springer Nature
ISSN:	2041-1723
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences Faculty of Medicine
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie Faculty of Medicine > Weitere > Centrum für integrierte Onkologie (CIO) Zentrum für Molekulare Medizin
Subjects:	Life sciences Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81454