Cullin E3 Ligase Activity Is Required for Myoblast Differentiation

The role of cullin E3-ubiquitin ligases for muscle homeostasis is best known during muscle atrophy, as the cullin-1 substrate adaptor atrogin-1 is among the most well-characterized muscle atrogins. We investigated whether cullin activity was also crucial during terminal myoblast differentiation and...

Full description

Saved in:
Bibliographic Details
Published in:Journal of molecular biology 2017-04, Vol.429 (7), p.1045-1066
Main Authors: Blondelle, Jordan, Shapiro, Paige, Domenighetti, Andrea A., Lange, Stephan
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation
Cells, Cultured
cullin
E3-ubiquitin ligase
Humans
Mice
MLN4924
muscle development
Myoblasts - enzymology
Myoblasts - physiology
Ubiquitin-Protein Ligases - metabolism
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 role of cullin E3-ubiquitin ligases for muscle homeostasis is best known during muscle atrophy, as the cullin-1 substrate adaptor atrogin-1 is among the most well-characterized muscle atrogins. We investigated whether cullin activity was also crucial during terminal myoblast differentiation and aggregation of acetylcholine receptors for the establishment of neuromuscular junctions in vitro. The activity of cullin E3-ligases is modulated through post-translational modification with the small ubiquitin-like modifier nedd8. Using either the Nae1 inhibitor MLN4924 (Pevonedistat) or siRNA against nedd8 in early or late stages of differentiation on C2C12 myoblasts, and primary satellite cells from mouse and human, we show that cullin E3-ligase activity is necessary for each step of the muscle cell differentiation program in vitro. We further investigate known transcriptional repressors for terminal muscle differentiation, namely ZBTB38, Bhlhe41, and Id1. Due to their identified roles for terminal muscle differentiation, we hypothesize that the accumulation of these potential cullin E3-ligase substrates may be partially responsible for the observed phenotype. MLN4924 is currently undergoing clinical trials in cancer patients, and our experiments highlight concerns on the homeostasis and regenerative capacity of muscles in these patients who often experience cachexia. [Display omitted] •Cullin–RING ligases play pivotal roles for terminal skeletal muscle differentiation.•Cullin inhibition blocks myotube formation and entry into the differentiation program.•Cullin inhibition interferes with acetylcholine receptor clustering.•Protein levels of myogenic repressors Bhlhe41 and Id1 are controlled by Cullin.•Cullin inhibition may have clinical implications for cancer patients.
ISSN:0022-2836
1089-8638
DOI:10.1016/j.jmb.2017.02.012