A complex of the ubiquitin ligase TRIM32 and the deubiquitinase USP7 balances the level of c-Myc ubiquitination and thereby determines neural stem cell fate specification.
Animals
Cell Nucleus
/ metabolism
Cell Proliferation
/ genetics
Cells, Cultured
Gene Ontology
HEK293 Cells
Humans
Lateral Ventricles
/ metabolism
Mice
Mice, Inbred C57BL
Neural Stem Cells
/ enzymology
Neurogenesis
/ genetics
Neurons
/ metabolism
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-myc
/ antagonists & inhibitors
Ubiquitin-Protein Ligases
/ antagonists & inhibitors
Ubiquitin-Specific Peptidase 7
/ antagonists & inhibitors
Ubiquitination
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
22
01
2017
accepted:
16
05
2018
revised:
27
04
2018
pubmed:
15
6
2018
medline:
4
6
2020
entrez:
15
6
2018
Statut:
ppublish
Résumé
The balance between stem cell maintenance and differentiation has been proposed to depend on antagonizing ubiquitination and deubiquitination reactions of key stem cell transcription factors (SCTFs) mediated by pairs of E3 ubiquitin ligases and deubiquitinating enzymes. Accordingly, increased ubiquitination results in proteasomal degradation of the SCTF, thereby inducing cellular differentiation, whereas increased deubiquitination stabilizes the SCTF, leading to maintenance of the stem cell fate. In neural stem cells, one of the key SCTFs is c-Myc. Previously, it has been shown that c-Myc is ubiquitinated by the E3 ligase TRIM32, thereby targeting c-Myc for proteasomal degradation and inducing neuronal differentiation. Accordingly, TRIM32 becomes upregulated during adult neurogenesis. This upregulation is accompanied by subcellular translocation of TRIM32 from the cytoplasm of neuroblasts to the nucleus of neurons. However, we observed that a subpopulation of proliferative type C cells already contains nuclear TRIM32. As these cells do not undergo neuronal differentiation, despite containing TRIM32 in the nucleus, where it can ubiquitinate c-Myc, we hypothesize that antagonizing factors, specifically deubiquitinating enzymes, are present in these particular cells. Here we show that TRIM32 associates with the deubiquitination enzyme USP7, which previously has been implicated in neural stem cell maintenance. USP7 and TRIM32 were found to exhibit a dynamic and partially overlapping expression pattern during neuronal differentiation both in vitro and in vivo. Most importantly, we are able to demonstrate that USP7 deubiquitinates and thereby stabilizes c-Myc and that this function is required to maintain neural stem cell fate. Accordingly, we propose the balanced ubiquitination and deubiquitination of c-Myc by TRIM32 and USP7 as a novel mechanism for stem cell fate determination.
Identifiants
pubmed: 29899379
doi: 10.1038/s41418-018-0144-1
pii: 10.1038/s41418-018-0144-1
pmc: PMC6460386
doi:
Substances chimiques
Myc protein, mouse
0
Proto-Oncogene Proteins c-myc
0
TRIM32 protein, mouse
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Ubiquitin-Specific Peptidase 7
EC 3.4.19.12
Usp7 protein, mouse
EC 3.4.19.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
728-740Références
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