The SH3 and multiple ankyrin repeat domains 3 (Shank3) proteins are core organizers of the postsynaptic density in neuronal excitatory synapses, and their defects cause various neurodevelopmental and neuropsychiatric disorders. Mechanistically, Shank3 directly and indirectly interacts with hundreds of synaptic proteins with diverse functions and potentially exerts its regulatory roles in synaptic development and function via these interactors. However, Shank3-dependent regulation of synaptic abundance has been validated in vivo for only a few Shank3 interactors. Here, using a quantitative proteomic analysis, we identified 136 proteins with altered synaptic abundance in the striatum of Shank3-overexpressing transgenic (TG) mice. By comparing these proteins with those found in a previous analysis of the postsynaptic density of Shank3 knock-out (KO) striatum, we identified and confirmed that cylindromatosis-associated deubiquitinase (Cyld), a deubiquitinase specific for Lys63-linked polyubiquitin chains, was up- and down-regulated in Shank3 TG and KO striatal synapses, respectively. Consistently, we found that the synaptic levels of Lys63-linked polyubiquitin chains were down- and up-regulated in the Shank3 TG and KO striata, respectively. Furthermore, by isolating and analyzing the synaptic Cyld complex, we generated a Cyld interactome consisting of 103 proteins, which may include Cyld substrates. Bioinformatic analyses suggested associations of the Cyld interactome with a few brain disorders and synaptic functions. Taken together, these results suggest that Shank3 regulates the synaptic abundance of Cyld in the mouse striatum and, thereby, potentially modulates the Lys63-linked polyubiquitination of striatal synaptic proteins.
Pubmed ID: 31215654 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This unknown targets Mouse IgG (H+L)
View all literature mentionsThis monoclonal targets TRAF6
View all literature mentionsThis polyclonal targets SHANK3
View all literature mentionsThis monoclonal targets K63-linkage Specific Polyubiquitin (D7A11) Rabbit mAb
View all literature mentionsThis monoclonal targets CYLD
View all literature mentionsThis recombinant monoclonal targets GAPDH
View all literature mentionsThis polyclonal targets CaMKII (phospho T286)
View all literature mentionsThis unknown targets CaMKII
View all literature mentionsThis monoclonal targets CYLD (D1A10) Rabbit mAb
View all literature mentionsThis monoclonal targets PSD-95
View all literature mentionslaboratory mouse with name C57BL/6JJmsSlc from MGI.
View all literature mentionsBioinformatics resource system including web server and web service for functional annotation and enrichment analyses of gene lists. Consists of comprehensive knowledgebase and set of functional analysis tools. Includes gene centered database integrating heterogeneous gene annotation resources to facilitate high throughput gene functional analysis.
View all literature mentionsOpen source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsKnowledge platform on psychiatric disorders and their genes. Resource for exploratory analysis of psychiatric diseases and their associated genes. PsyGeNET is composed of database and set of analysis tools and is the result of the integration of information from DisGeNET and data extracted from the literature by text mining, followed by curation by domain experts.
View all literature mentions