Cognitive dysfunction (CD) is common among patients with the autoimmune disease systemic lupus erythematosus (SLE). Anti-ribosomal P autoantibodies associate with this dysfunction and have neuropathogenic effects that are mediated by cross-reacting with neuronal surface P antigen (NSPA) protein. Elucidating the function of NSPA can then reveal CD pathogenic mechanisms and treatment opportunities. In the brain, NSPA somehow contributes to glutamatergic NMDA receptor (NMDAR) activity in synaptic plasticity and memory. Here we analyze the consequences of NSPA absence in KO mice considering its structural features shared with E3 ubiquitin ligases and the crucial role of ubiquitination in synaptic plasticity. Electrophysiological studies revealed a decreased long-term potentiation in CA3-CA1 and medial perforant pathway-dentate gyrus (MPP-DG) hippocampal circuits, reflecting glutamatergic synaptic plasticity impairment in NSPA-KO mice. The hippocampal dentate gyrus of these mice showed a lower number of Arc-positive cells indicative of decreased synaptic activity and also showed proliferation defects of neural progenitors underlying less adult neurogenesis. All this translates into poor spatial and recognition memory when NSPA is absent. A cell-based assay demonstrated ubiquitination of NSPA as a property of RBR-type E3 ligases, while biochemical analysis of synaptic regions disclosed the tyrosine phosphatase PTPMEG as a potential substrate. Mice lacking NSPA have increased levels of PTPMEG due to its reduced ubiquitination and proteasomal degradation, which correlated with lower levels of GluN2A and GluN2B NMDAR subunits only at postsynaptic densities (PSDs), indicating selective trafficking of these proteins out of PSDs. As both GluN2A and GluN2B interact with PTPMEG, tyrosine (Tyr) dephosphorylation likely drives their endocytic removal from the PSD. Actually, immunoblot analysis showed reduced phosphorylation of the GluN2B endocytic signal Tyr1472 in NSPA-KO mice. NSPA contributes to hippocampal plasticity and memory processes ensuring appropriate levels of adult neurogenesis and PSD-located NMDAR. PTPMEG qualifies as NSPA ubiquitination substrate that regulates Tyr phosphorylation-dependent NMDAR stability at PSDs. The NSPA/PTPMEG pathway emerges as a new regulator of glutamatergic transmission and plasticity and may provide mechanistic clues and therapeutic opportunities for anti-P-mediated pathogenicity in SLE, a still unmet need.

中文翻译：

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神经元表面P抗原（NSPA）通过酪氨酸磷酸酶PTPMEG的泛素化调节突触后NMDAR的稳定性

自身免疫性疾病系统性红斑狼疮（SLE）患者常见认知功能障碍（CD）。抗核糖体P自身抗体与此功能障碍相关，并具有神经病原性作用，该作用是通过与神经元表面P抗原（NSPA）蛋白发生交叉反应而介导的。阐明NSPA的功能可以揭示CD的致病机制和治疗机会。在大脑中，NSPA以某种方式有助于谷氨酸能NMDA受体（NMDAR）在突触可塑性和记忆中的活性。在这里，我们考虑到与E3泛素连接酶共有的结构特征以及泛素化在突触可塑性中的关键作用，分析了KO小鼠中NSPA缺失的后果。电生理研究显示CA3-CA1和内侧穿孔通路齿状回（MPP-DG）海马回路的长期增强作用减弱，反映了NSPA-KO小鼠的谷氨酸能突触可塑性受损。这些小鼠的海马齿状回显示出较少的Arc阳性细胞，表明突触活性降低，还显示了成年神经发生较少的神经祖细胞的增殖缺陷。缺少NSPA时，所有这些都会转化为较差的空间和识别记忆。基于细胞的分析表明，NSPA的泛素化是RBR型E3连接酶的一种特性，而突触区的生化分析表明酪氨酸磷酸酶PTPMEG是潜在的底物。缺乏NSPA的小鼠由于泛素化程度降低和蛋白酶体降解而使PTPMEG的水平升高，这与仅在突触后密度（PSDs）下与较低水平的GluN2A和GluN2B NMDAR亚基相关，表明这些蛋白质选择性地从PSDs中转运出来。由于GluN2A和GluN2B都与PTPMEG相互作用，酪氨酸（Tyr）的去磷酸化可能会驱动其从PSD的胞吞清除。实际上，免疫印迹分析显示NSPA-KO小鼠中GluN2B内吞信号Tyr1472的磷酸化降低。NSPA有助于海马的可塑性和记忆过程，确保适当水平的成人神经发生和位于PSD的NMDAR。PTPMEG有资格作为NSPA泛素化底物，可调节PSD上Tyr磷酸化依赖性的NMDAR稳定性。