USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-dependent Protein Levels
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 mul...
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| Format: | Article |
| Language: | English |
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Society for Neuroscience
2021
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| Online Access: | https://hdl.handle.net/1721.1/135298 |
| _version_ | 1826196829780312064 |
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| author | Kerrisk Campbell, Meghan Sheng, Morgan |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Kerrisk Campbell, Meghan Sheng, Morgan |
| author_sort | Kerrisk Campbell, Meghan |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:38:36Z |
| format | Article |
| id | mit-1721.1/135298 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:38:36Z |
| publishDate | 2021 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/1352982023-09-28T19:59:19Z USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-dependent Protein Levels Kerrisk Campbell, Meghan Sheng, Morgan Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Massachusetts Institute of Technology. Department of Biology 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. 2021-10-27T20:22:51Z 2021-10-27T20:22:51Z 2018 2021-03-30T14:49:13Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135298 en 10.1523/JNEUROSCI.3305-17.2018 Journal of Neuroscience Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Society for Neuroscience Journal of Neuroscience |
| spellingShingle | Kerrisk Campbell, Meghan Sheng, Morgan USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-dependent Protein Levels |
| title | USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-dependent Protein Levels |
| title_full | USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-dependent Protein Levels |
| title_fullStr | USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-dependent Protein Levels |
| title_full_unstemmed | USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-dependent Protein Levels |
| title_short | USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-dependent Protein Levels |
| title_sort | usp8 deubiquitinates shank3 to control synapse density and shank3 activity dependent protein levels |
| url | https://hdl.handle.net/1721.1/135298 |
| work_keys_str_mv | AT kerriskcampbellmeghan usp8deubiquitinatesshank3tocontrolsynapsedensityandshank3activitydependentproteinlevels AT shengmorgan usp8deubiquitinatesshank3tocontrolsynapsedensityandshank3activitydependentproteinlevels |