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Cell Death Differ. 2018 Aug;25(8):1394-1407. doi: 10.1038/s41418-017-0046-7. Epub 2018 Jan 19.

Cylindromatosis mediates neuronal cell death in vitro and in vivo.

Author information

1
Institute for Pharmacology and Clinical Pharmacy, Biochemical-Pharmacological Center Marburg, Marburg Center for Mind, Brain and Behavior - MCMBB, University of Marburg, Marburg, Germany.
2
Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany.
3
Institute for Veterinarian Pathology, University of Gießen, Gießen, Germany.
4
Institute for Veterinarian Physiology, University of Gießen, Gießen, Germany.
5
Institute for Pharmacology and Clinical Pharmacy, Biochemical-Pharmacological Center Marburg, Marburg Center for Mind, Brain and Behavior - MCMBB, University of Marburg, Marburg, Germany. culmsee@uni-marburg.de.

Abstract

The tumor-suppressor cylindromatosis (CYLD) is a deubiquitinating enzyme and key regulator of cell proliferation and inflammation. A genome-wide siRNA screen linked CYLD to receptor interacting protein-1 (RIP1) kinase-mediated necroptosis; however, the exact mechanisms of CYLD-mediated cell death remain unknown. Therefore, we investigated the precise role of CYLD in models of neuronal cell death in vitro and evaluated whether CYLD deletion affects brain injury in vivo. In vitro, downregulation of CYLD increased RIP1 ubiquitination, prevented RIP1/RIP3 complex formation, and protected neuronal cells from oxidative death. Similar protective effects were achieved by siRNA silencing of RIP1 or RIP3 or by pharmacological inhibition of RIP1 with necrostatin-1. In vivo, CYLD knockout mice were protected from trauma-induced brain damage compared to wild-type littermate controls. These findings unravel the mechanisms of CYLD-mediated cell death signaling in damaged neurons in vitro and suggest a cell death-mediating role of CYLD in vivo.

PMID:
29352268
PMCID:
PMC6113218
DOI:
10.1038/s41418-017-0046-7
[Indexed for MEDLINE]
Free PMC Article

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