Universität zu Köln

Kieckhofer, Emilia, Slaats, Gisela G., Ebert, Lena K., Albert, Marie-Christine, Dafinger, Claudia, Kashkar, Hamid, Benzing, Thomas ORCID: 0000-0003-0512-1066 and Schermer, Bernhard (2022). Primary cilia suppress Ripk3-mediated necroptosis. Cell Death Discov., 8 (1). LONDON: SPRINGERNATURE. ISSN 2058-7716

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Abstract

Cilia are sensory organelles that project from the surface of almost all cells. Nephronophthisis (NPH) and NPH-related ciliopathies are degenerative genetic diseases caused by mutation of cilia-associated genes. These kidney disorders are characterized by progressive loss of functional tubular epithelial cells which is associated with inflammation, progressive fibrosis, and cyst formation, ultimately leading to end-stage renal disease. However, disease mechanisms remain poorly understood. Here, we show that targeted deletion of cilia in renal epithelial cells enhanced susceptibility to necroptotic cell death under inflammatory conditions. Treatment of non-ciliated cells with tumor necrosis factor (TNF) alpha and the SMAC mimetic birinapant resulted in Ripk1-dependent cell death, while viability of ciliated cells was almost not affected. Cell death could be enhanced and shifted toward necroptosis by the caspase inhibitor emricasan, which could be blocked by inhibitors of Ripk1 and Ripk3. Moreover, combined treatment of ciliated and non-ciliated cells with TNF alpha and cycloheximide induced a cell death response that could be partially rescued with emricasan in ciliated cells. In contrast, non-ciliated cells responded with pronounced cell death that was blocked by necroptosis inhibitors. Consistently, combined treatment with interferon-gamma and emricasan induced cell death only in non-ciliated cells. Mechanistically, enhanced necroptosis induced by loss of cilia could be explained by induction of Ripk3 and increased abundance of autophagy components, including p62 and LC3 associated with the Ripk1/Ripk3 necrosome. Genetic ablation of cilia in renal tubular epithelial cells in mice resulted in TUNEL positivity and increased expression of Ripk3 in kidney tissue. Moreover, loss of Nphp1, the most frequent cause of NPH, further increased susceptibility to necroptosis in non-ciliated epithelial cells, suggesting that necroptosis might contribute to the pathogenesis of the disease. Together, these data provide a link between cilia-related signaling and cell death responses and shed new light on the disease pathogenesis of NPH-related ciliopathies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kieckhofer, Emilia UNSPECIFIED UNSPECIFIED UNSPECIFIED Slaats, Gisela G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ebert, Lena K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Albert, Marie-Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Dafinger, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Kashkar, Hamid UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED orcid.org/0000-0003-0512-1066 UNSPECIFIED Schermer, Bernhard UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-671453
DOI:	10.1038/s41420-022-01272-2
Journal or Publication Title:	Cell Death Discov.
Volume:	8
Number:	1
Date:	2022
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	2058-7716
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; KIDNEY-SPECIFIC INACTIVATION; CELL-DEATH; KIF3A SUBUNIT; APOPTOSIS; DISEASE; AUTOPHAGY; BINDING; TISSUE; MORPHOGENESIS Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67145