Neuroligins （Nlgs） are transmembrane cell adhesion molecules playing essential roles in synapse development and function. Genetic mutations in neuroUgin genes have been linked with some neurodevelopmental disorders ...Neuroligins （Nlgs） are transmembrane cell adhesion molecules playing essential roles in synapse development and function. Genetic mutations in neuroUgin genes have been linked with some neurodevelopmental disorders such as autism. These mutated Nlgs are mostly retained in the endoplasmic reticulum （ER）. However, the mechanisms underlying normal Nlg maturation and trafficking have remained largely unknown. Here, we found that Drosophila neuroligin 2 （DNlg2） undergoes proteolytic cleavage in the ER in a variety of Drosophila tissues throughout developmental stages. A region encompassing Y642-T698 is required for this process. The immature non-cleavable DNtg2 is retained in the ER and non-functionaL The C-terminal fragment of DNlg2 instead of the full-length or non-cleavable DNIg2 is able to rescue neuromuscular junction defects and GluRIIB reduction induced by dnlg2 deletion. Intriguingly, the autism-associated R598C mutation in DNIg2 leads to similar marked defects in DNIg2 proteo- lytic process and ER export, revealing a potential role of the improper Nlg cleavage in autism pathogenesis. Collectively, our find- ings uncover a specific mechanism that controls DNIg2 maturation and trafficking via proteolytic cleavage in the ER, suggesting that the perturbed proteolytic cleavage of Nlgs likely contributes to autism disorder.展开更多
文摘Neuroligins （Nlgs） are transmembrane cell adhesion molecules playing essential roles in synapse development and function. Genetic mutations in neuroUgin genes have been linked with some neurodevelopmental disorders such as autism. These mutated Nlgs are mostly retained in the endoplasmic reticulum （ER）. However, the mechanisms underlying normal Nlg maturation and trafficking have remained largely unknown. Here, we found that Drosophila neuroligin 2 （DNlg2） undergoes proteolytic cleavage in the ER in a variety of Drosophila tissues throughout developmental stages. A region encompassing Y642-T698 is required for this process. The immature non-cleavable DNtg2 is retained in the ER and non-functionaL The C-terminal fragment of DNlg2 instead of the full-length or non-cleavable DNIg2 is able to rescue neuromuscular junction defects and GluRIIB reduction induced by dnlg2 deletion. Intriguingly, the autism-associated R598C mutation in DNIg2 leads to similar marked defects in DNIg2 proteo- lytic process and ER export, revealing a potential role of the improper Nlg cleavage in autism pathogenesis. Collectively, our find- ings uncover a specific mechanism that controls DNIg2 maturation and trafficking via proteolytic cleavage in the ER, suggesting that the perturbed proteolytic cleavage of Nlgs likely contributes to autism disorder.
