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Trim17, novel E3 ubiquitin-ligase, initiates neuronal apoptosis

Lassot, I; Robbins, I; Kristiansen, M; Rahmeh, R; Jaudon, F; Magiera, M; Mora, S; ... Desagher, S; + view all (2010) Trim17, novel E3 ubiquitin-ligase, initiates neuronal apoptosis. Cell Death and Differentiation , 17 (12) 1928 - 1941. 10.1038/cdd.2010.73. Green open access

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Abstract

Accumulating data indicate that the ubiquitin-proteasome system controls apoptosis by regulating the level and the function of key regulatory proteins. In this study, we identified Trim17, a member of the TRIM/RBCC protein family, as one of the critical E3 ubiquitin ligases involved in the control of neuronal apoptosis upstream of mitochondria. We show that expression of Trim17 is increased both at the mRNA and protein level in several in vitro models of transcription-dependent neuronal apoptosis. Expression of Trim17 is controlled by the PI3K/Akt/GSK3 pathway in cerebellar granule neurons (CGN). Moreover, the Trim17 protein is expressed in vivo, in apoptotic neurons that naturally die during post-natal cerebellar development. Overexpression of active Trim17 in primary CGN was sufficient to induce the intrinsic pathway of apoptosis in survival conditions. This pro-apoptotic effect was abolished in Bax(-/-) neurons and depended on the E3 activity of Trim17 conferred by its RING domain. Furthermore, knock-down of endogenous Trim17 and overexpression of dominant-negative mutants of Trim17 blocked trophic factor withdrawal-induced apoptosis both in CGN and in sympathetic neurons. Collectively, our data are the first to assign a cellular function to Trim17 by showing that its E3 activity is both necessary and sufficient for the initiation of neuronal apoptosis. Cell Death and Differentiation (2010) 17, 1928-1941; doi: 10.1038/cdd.2010.73; published online 18 June 2010

Type: Article
Title: Trim17, novel E3 ubiquitin-ligase, initiates neuronal apoptosis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/cdd.2010.73
Publisher version: http://dx.doi.org/10.1038/cdd.2010.73
Language: English
Additional information: Author manuscript made available here under publisher's terms of use, please see http://www.nature.com/authors/editorial_policies/license.html#terms
Keywords: apoptosis, neurons, ubiquitin-proteasome system, E3 ubiquitin-ligase, Trim17, cerebellum, GLYCOGEN-SYNTHASE KINASE-3, CEREBELLAR GRANULE NEURONS, PROGRAMMED CELL-DEATH, GROWTH-FACTOR-I, SYMPATHETIC NEURONS, CYTOCHROME-C, SURVIVAL, PROTEIN, PROTEASOME, PATHWAY
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/19932
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