Shank3 regulates striatal synaptic abundance of Cyld, a deubiquitinase specific for Lys63-linked polyubiquitin chains

Chunmei Jin, Shinhyun Kim, Hyojin Kang, Ki Na Yun, Yeunkum Lee, Yinhua Zhang, Yoonhee Kim, Jin Young Kim, Kihoon Han

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

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. (Figure presented.).

Original languageEnglish
Pages (from-to)776-786
Number of pages11
JournalJournal of Neurochemistry
Volume150
Issue number6
DOIs
Publication statusPublished - 2019 Sept 1

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government Ministry of Science and ICT (NRF-2018R1C1B6001235, NRF-2018M3C7A1024603, NRF-2015M3C7A1028790) and by Korea Basic Science Institute (KBSI) research grant (T39710). The authors have no conflicts of interest to declare. All experiments were conducted in compliance with the ARRIVE guidelines.

Publisher Copyright:
© 2019 International Society for Neurochemistry

Keywords

  • Cyld
  • Lys63-linked polyubiquitin chain
  • Shank3
  • deubiquitinase
  • striatum

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'Shank3 regulates striatal synaptic abundance of Cyld, a deubiquitinase specific for Lys63-linked polyubiquitin chains'. Together they form a unique fingerprint.

Cite this