Synaptogenesis is initiated by adhesive contact between pre-and postsynaptic membrane and is essential for neuronal network formation in the brain. Abnormal synaptogenesis could lead to brain disorders such as Autism. Neuroligins, a family of postsynaptic adhesion proteins, are thought to play an important role in synapse generation via trans-interaction with presynaptic proteins neurexins. Mutations of neuroligins were found in patients with Autism. Neuroligin2, a member of neuroligin family, is exclusively expressed at the inhibitory synapses and regulates the formation of inhibitory synapses. To understand the mechanism underlying neurologin2’s function, we performed IP-MS and found that neuroligin2 interacted with the ubiquitin specific peptidase 8 (USP8), which could remove...[ Read more ]

Synaptogenesis is initiated by adhesive contact between pre-and postsynaptic membrane and is essential for neuronal network formation in the brain. Abnormal synaptogenesis could lead to brain disorders such as Autism. Neuroligins, a family of postsynaptic adhesion proteins, are thought to play an important role in synapse generation via trans-interaction with presynaptic proteins neurexins. Mutations of neuroligins were found in patients with Autism. Neuroligin2, a member of neuroligin family, is exclusively expressed at the inhibitory synapses and regulates the formation of inhibitory synapses. To understand the mechanism underlying neurologin2’s function, we performed IP-MS and found that neuroligin2 interacted with the ubiquitin specific peptidase 8 (USP8), which could remove ubiquitin from its substrates to regulate protein trafficking or degradation. We performed immunoprecipitation to verify that USP8 interacted with neruoligin2 specifically. We also determined the regions that responsible for their interaction. Overexpression and knockdown experiments were then performed to demonstrate that USP8 could robustly regulate neuroligin2 ubiquitination. Our data also suggested that USP8 could control inhibitory synapse formation by regulating the endocytosis of neuroligin2.