Universität zu Köln

Koerner, Lioba ORCID: 0000-0003-4364-479X, Li, Xiaoming ORCID: 0009-0002-3229-5440, Silnov, Eveline ORCID: 0009-0004-2326-1200, Laurien, Lucie ORCID: 0009-0003-1926-6677 and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2025). RIPK1 autophosphorylation at S161 mediates cell death and inflammation. Journal of Experimental Medicine, 222 (12). pp. 1-18. Rockefeller University Press. ISSN 0022-1007

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Abstract

[Artikel-Nr. e20250279] RIPK1 regulates cell death and inflammation and has been implicated in the pathogenesis of inflammatory diseases. RIPK1 autophosphorylation promotes cell death induction; however, the underlying mechanisms and the role of specific autophosphorylation sites remain elusive. Using knock-in mouse models, here we show that S161 autophosphorylation has a critical physiological function in RIPK1-mediated cell death and inflammation. S161N substitution partially suppressed RIPK1-mediated catalytic activity and cell death induction but was sufficient to prevent skin inflammation induced by keratinocyte necroptosis or apoptosis in relevant mouse models. Combined S161N and S166A mutations synergized to prevent RIPK1-mediated cell death more efficiently than the single site mutations, revealing functional redundancy. Moreover, phosphomimetic S161E mutation could overcome the necroptosis-inhibitory effect of S166A mutation, revealing that S161 phosphorylation is sufficient for necroptosis induction. Collectively, a functional interplay of S161 and S166 phosphorylation events regulates RIPK1-dependent cell death and inflammation.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Koerner, Lioba UNSPECIFIED https://orcid.org/0000-0003-4364-479X UNSPECIFIED Li, Xiaoming UNSPECIFIED https://orcid.org/0009-0002-3229-5440 UNSPECIFIED Silnov, Eveline UNSPECIFIED https://orcid.org/0009-0004-2326-1200 UNSPECIFIED Laurien, Lucie UNSPECIFIED https://orcid.org/0009-0003-1926-6677 UNSPECIFIED Pasparakis, Manolis UNSPECIFIED https://orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-799236
Identification Number:	10.1084/jem.20250279
Journal or Publication Title:	Journal of Experimental Medicine
Volume:	222
Number:	12
Page Range:	pp. 1-18
Date:	1 December 2025
Publisher:	Rockefeller University Press
ISSN:	0022-1007
Language:	English
Faculty:	Central Institutions / Interdisciplinary Research Centers Faculty of Mathematics and Natural Sciences
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:	Life sciences
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/79923