Primary cilia suppress Ripk3-mediated necroptosis

• DOI: 10.1038/s41420-022-01272-2
• Publication Date: 2022-12-02T10:29:11Z
• Authors: Emilia Kieckhöfer; Gisela G. Slaats; Lena K. Ebert; Marie-Christine A...; Claudia Dafinger; Hamid Kashkar; Thomas Benzing; Bernhard Schermer
• Keywords: RIPK1; Ciliopathies

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