Universität zu Köln

Eren, Remzi Onur ORCID: 0000-0003-2795-0156, Kaya, Göksu Gökberk ORCID: 0000-0003-2976-9318, Schwarzer, Robin ORCID: 0009-0000-8139-2891 and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2024). IKKε and TBK1 prevent RIPK1 dependent and independent inflammation. Nature Communications, 15 (1). pp. 1-18. Springer Nature. ISSN 2041-1723

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Abstract

[Artikel-Nr.: 130] TBK1 and IKKε regulate multiple cellular processes including anti-viral type-I interferon responses, metabolism and TNF receptor signaling. However, the relative contributions and potentially redundant functions of IKKε and TBK1 in cell death, inflammation and tissue homeostasis remain poorly understood. Here we show that IKKε compensates for the loss of TBK1 kinase activity to prevent RIPK1-dependent and -independent inflammation in mice. Combined inhibition of IKKε and TBK1 kinase activities caused embryonic lethality that was rescued by heterozygous expression of kinase-inactive RIPK1. Adult mice expressing kinase-inactive versions of IKKε and TBK1 developed systemic inflammation that was induced by both RIPK1-dependent and -independent mechanisms. Combined inhibition of IKKε and TBK1 kinase activities in myeloid cells induced RIPK1-dependent cell death and systemic inflammation mediated by IL-1 family cytokines. Tissue-specific studies showed that IKKε and TBK1 were required to prevent cell death and inflammation in the intestine but were dispensable for liver and skin homeostasis. Together, these findings revealed that IKKε and TBK1 exhibit tissue-specific functions that are important to prevent cell death and inflammation and maintain tissue homeostasis.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Eren, Remzi Onur UNSPECIFIED https://orcid.org/0000-0003-2795-0156 UNSPECIFIED Kaya, Göksu Gökberk UNSPECIFIED https://orcid.org/0000-0003-2976-9318 UNSPECIFIED Schwarzer, Robin UNSPECIFIED https://orcid.org/0009-0000-8139-2891 UNSPECIFIED Pasparakis, Manolis UNSPECIFIED https://orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-814650
Identification Number:	10.1038/s41467-023-44372-y
Journal or Publication Title:	Nature Communications
Volume:	15
Number:	1
Page Range:	pp. 1-18
Number of Pages:	18
Date:	2 January 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 Biology > Institute for Genetics Zentrum für Molekulare Medizin
Subjects:	Medical sciences Medicine Management and auxiliary services
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81465