Cylindromatosis mediates neuronal cell death in vitro and in vivo

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 re...

Full description

Saved in:
Bibliographic Details
Published in:Cell death and differentiation 2018-08, Vol.25 (8), p.1394-1407
Main Authors: Ganjam, Goutham K., Terpolilli, Nicole Angela, Diemert, Sebastian, Eisenbach, Ina, Hoffmann, Lena, Reuther, Christina, Herden, Christiane, Roth, Joachim, Plesnila, Nikolaus, Culmsee, Carsten
Format: Article
Language:English
Subjects:
13/1
38/77
42/89
631/378/2611
631/45/275
64/60
692/699/375
82/29
96/106
96/109
96/63
Animal models
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell culture
Cell Cycle Analysis
Cell death
Cell proliferation
Clonal deletion
Genetic screening
Genomes
Kinases
Life Sciences
Necroptosis
siRNA
Stem Cells
Traumatic brain injury
Ubiquitination
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-017-0046-7