USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-dependent Protein Levels
Name
5289.full.pdf
Description
Published version
Size
1.89 MB
Format
Adobe PDF
Checksum (MD5)
4176bb536fdddc32a71bcd3a52ee2c97
Author(s)
Kerrisk Campbell, Meghan
Sheng, Morgan
Date Issued
2018
Journal
Journal of Neuroscience
Publisher
Society for Neuroscience
Version
Final published version
Abstract
Mutations or altered protein levels of SHANK3 are implicated in neurodevelopmental disorders such as Phelan–McDermid syndrome, autism spectrum disorders, and schizophrenia (Guilmatre et al., 2014). Loss of SHANK3 in mouse models results in decreased synapse density and reduction in the levels of multiple synaptic proteins (Jiang and Ehlers, 2013). The family of SHANK scaffolding molecules are among the most heavily ubiquitinated proteins at the postsynaptic density. The ubiquitin-dependent proteasome degradation of SHANK is regulated by synaptic activity and may contribute to activity-dependent synaptic remodeling (Ehlers, 2003; Shin et al., 2012). However, the identity of the specific deubiquitinating enzymes and E3 ligases that regulate SHANK ubiquitination at synapses are unknown. Here we identify USP8/UBPY as a deubiquitinating enzyme that regulates SHANK3 and SHANK1 ubiquitination and protein levels. In primary rat neurons, USP8 enhances SHANK3 and SHANK1 protein levels via deubiquitination and increases dendritic spine density. Additionally, USP8 is essential for changes in SHANK3 protein levels following synaptic activity modulation. These data identify USP8 as a key modulator of SHANK3 downstream of synaptic activity.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1523/JNEUROSCI.3305-17.2018
