Universität zu Köln

Veli, Önay ORCID: 0009-0001-4748-8950, Kaya, Öykü ORCID: 0009-0005-6665-4634, Varanda, Ana Beatriz ORCID: 0000-0002-5981-6368, Hildebrandt, Ximena ORCID: 0000-0001-6930-203X, Xiao, Peng, Estornes, Yann, Poggenberg, Matea ORCID: 0000-0001-5548-9681, Wang, Yuan, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Bertrand, Mathieu J.M., Walczak, Henning ORCID: 0000-0002-6312-4591, Annibaldi, Alessandro ORCID: 0000-0002-0346-4340, Cardozo, Alessandra K. and Peltzer, Nieves ORCID: 0000-0002-4134-5852 (2024). RIPK1 is dispensable for cell death regulation in β-cells during hyperglycemia. Molecular Metabolism, 87. pp. 1-11. Elsevier. ISSN 2212-8778

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Abstract

[Artikel-Nr.: 101988] Objective: Receptor-interacting protein kinase 1 (RIPK1) orchestrates the decision between cell survival and cell death in response to tumor necrosis factor (TNF) and other cytokines. Whereas the scaffolding function of RIPK1 is crucial to prevent TNF-induced apoptosis and necroptosis, its kinase activity is required for necroptosis and partially for apoptosis. Although TNF is a proinflammatory cytokine associated with b-cell loss in diabetes, the mechanism by which TNF induces b-cell demise remains unclear. Methods: Here, we dissected the contribution of RIPK1 scaffold versus kinase functions to b-cell death regulation using mice lacking RIPK1 specifically in b-cells (Ripk1b-KO mice) or expressing a kinase-dead version of RIPK1 (Ripk1D138N mice), respectively. These mice were challenged with streptozotocin, a model of autoimmune diabetes. Moreover, Ripk1b-KO mice were further challenged with a high-fat diet to induce hyperglycemia. For mechanistic studies, pancreatic islets were subjected to various killing and sensitising agents. Results: Inhibition of RIPK1 kinase activity (Ripk1D138N mice) did not affect the onset and progression of hyperglycemia in a type 1 diabetes model. Moreover, the absence of RIPK1 expression in b-cells did not affect normoglycemia under basal conditions or hyperglycemia under diabetic challenges. Ex vivo, primary pancreatic islets are not sensitised to TNF-induced apoptosis and necroptosis in the absence of RIPK1. Intriguingly, we found that pancreatic islets display high levels of the antiapoptotic cellular FLICE-inhibitory protein (cFLIP) and low levels of apoptosis (Caspase-8) and necroptosis (RIPK3) components. Cycloheximide treatment, which led to a reduction in cFLIP levels, rendered primary islets sensitive to TNF-induced cell death which was fully blocked by caspase inhibition. Conclusions: Unlike in many other cell types (e.g., epithelial, and immune), RIPK1 is not required for cell death regulation in b-cells under physiological conditions or diabetic challenges. Moreover, in vivo and in vitro evidence suggest that pancreatic b-cells do not undergo necroptosis but mainly caspase-dependent death in response to TNF. Last, our results show that b-cells have a distinct mode of regulation of TNF-cytotoxicity that is independent of RIPK1 and that may be highly dependent on cFLIP.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Veli, Önay UNSPECIFIED https://orcid.org/0009-0001-4748-8950 UNSPECIFIED Kaya, Öykü UNSPECIFIED https://orcid.org/0009-0005-6665-4634 UNSPECIFIED Varanda, Ana Beatriz UNSPECIFIED https://orcid.org/0000-0002-5981-6368 UNSPECIFIED Hildebrandt, Ximena UNSPECIFIED https://orcid.org/0000-0001-6930-203X UNSPECIFIED Xiao, Peng UNSPECIFIED UNSPECIFIED UNSPECIFIED Estornes, Yann UNSPECIFIED UNSPECIFIED UNSPECIFIED Poggenberg, Matea UNSPECIFIED https://orcid.org/0000-0001-5548-9681 UNSPECIFIED Wang, Yuan UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED https://orcid.org/0000-0002-9870-0966 UNSPECIFIED Bertrand, Mathieu J.M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Walczak, Henning UNSPECIFIED https://orcid.org/0000-0002-6312-4591 UNSPECIFIED Annibaldi, Alessandro UNSPECIFIED https://orcid.org/0000-0002-0346-4340 UNSPECIFIED Cardozo, Alessandra K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Peltzer, Nieves UNSPECIFIED https://orcid.org/0000-0002-4134-5852 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-814291
Identification Number:	10.1016/j.molmet.2024.101988
Journal or Publication Title:	Molecular Metabolism
Volume:	87
Page Range:	pp. 1-11
Number of Pages:	11
Date:	September 2024
Publisher:	Elsevier
ISSN:	2212-8778
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 Faculty of Medicine > Weitere > Translationale Genomik Zentrum für Molekulare Medizin Faculty of Medicine > Biochemie > Institut I für Biochemie
Subjects:	Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language RIPK1 ; Necroptosis ; TNF ; Apoptosis ; β-cell ; Diabetes ; cFLIP English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81429