Sez6l2 regulates phosphorylation of ADD and neuritogenesis
Sez6l2 regulates phosphorylation of ADD and neuritogenesis
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Sez6l2 调节 ADD 和神经突发生的磷酸化
DOI：
10.1016/j.bbrc.2017.10.047
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
S.
中科院分区：
文献类型：
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作者：
Yaguchi;H.;Yabe;I.;Takahashi;H.;Watanabe;M.;Nomura;T.;Kano;T.;Matsumoto;M.;Nakayama;K.I.;Watanabe;M. and Hatakeyama;S.
越来越多的证据表明，免疫介导的机制可能参与了包括小脑性共济失调在内的中枢神经系统疾病的发病，神经元表面抗体的异常产生表明了这一点。我们之前报告了一例小脑性共济失调患者，与产生一种新的抗神经元抗体，抗癫痫相关的6同系物2(Sez612)有关。Sez6l2是一种1型膜蛋白，在海马区和小脑皮质中高表达，缺乏Sez6l2蛋白家族成员的小鼠会发生共济失调。在这里，我们使用了一种基于蛋白质组学的方法来证明来自该患者的血清识别Sez6l2的胞外结构域，并且Sez6l2蛋白同时与内收蛋白(ADD)和谷氨酸受体1(GluR1)结合。我们的结果表明，Sez6l2是AMPA受体的辅助亚基之一，并作为连接GluR1与ADD的支架蛋白。此外，Sez6l2的过度表达上调了Add的磷酸化，而siRNA介导的Sez612的下调阻止了Add的磷酸化，这表明Sez6l2调控了AMPA-Add的信号转导。
Increasing evidence shows that immune-mediated mechanisms may contribute to the pathogenesis of central nervous system disorders including cerebellar ataxias, as indicated by the aberrant production of neuronal surface antibodies. We previously reported a patient with cerebellar ataxia associated with production of a new anti-neuronal antibody, anti-seizure-related 6 homolog like 2 (Sez6l2). Sez6l2 is a type 1 membrane protein that is highly expressed in the hippocampus and cerebellar cortex and mice lacking Sez6l2 protein family members develop ataxia. Here we used a proteomics-based approach to show that serum derived from this patient recognizes the extracellular domain of Sez6l2 and that Sez6l2 protein binds to both adducin (ADD) and glutamate receptor 1 (GluR1). Our results indicate that Sez6l2 is one of the auxiliary subunits of the AMPA receptor and acts as a scaffolding protein to link GluR1 to ADD. Furthermore, Sez6l2 overexpression upregulates ADD phosphorylation, whereas siRNA-mediated downregulation of Sez612 prevents ADD phosphorylation, suggesting that Sez6l2 modulates AMPA-ADD signal transduction.