Disease-associated synaptic scaffold protein CNK2 modulates PSD size and influences localisation of the regulatory kinase TNIK
Disease-associated synaptic scaffold protein CNK2 modulates PSD size and influences localisation of the regulatory kinase TNIK
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DOI：
10.1038/s41598-020-62207-4
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发表时间：
2020-03-31
影响因子：
4.6
通讯作者：
Shoichet, Sarah A.
中科院分区：
文献类型：
--
作者：
Zieger, Hanna L.;Kunde, Stella-Amrei;Shoichet, Sarah A.
支架蛋白负责细胞内的结构组织;它们与其他蛋白质形成复合物，以促进信号通路和催化反应。Ras 2激酶抑制因子的支架蛋白连接增强子（CNK 2）主要在神经组织中表达，最近被认为与X连锁智力残疾（ID）有关。我们研究了CNK 2在神经元中的作用，以帮助我们理解CNK 2的改变如何导致发育缺陷，我们已经阐明了CNK 2在控制突触后密度（PSD）形态的分子过程中的功能作用。我们还确定了新的CNK 2相互作用伙伴，并探讨了它们与CNK 2的功能相互依赖性。我们专注于新的相互作用伙伴TRAF 2和NCK相互作用激酶TNIK，这也与ID。CNK 2和TNIK都表达在神经元树突和集中在树突棘，和染色与突触标记物表明一个明确的突触后定位。重要的是，我们的数据强调CNK 2在指导TNIK亚细胞定位中起作用，并且在神经元中，CNK 2参与确保这种多功能激酶以理想的水平存在于正确的位置。总之，我们的数据表明CNK 2表达对于调节PSD形态是至关重要的;此外，我们的研究强调CNK 2作为支架发挥作用，具有指导细胞内调节蛋白定位的潜力。重要的是，我们描述了CNK 2和调节激酶TNIK之间的新联系，并提供证据支持CNK 2定位和表达的改变有可能影响TNIK和其他重要的调节分子在神经元中的行为。
Scaffold proteins are responsible for structural organisation within cells; they form complexes with other proteins to facilitate signalling pathways and catalytic reactions. The scaffold protein connector enhancer of kinase suppressor of Ras 2 (CNK2) is predominantly expressed in neural tissues and was recently implicated in X-linked intellectual disability (ID). We have investigated the role of CNK2 in neurons in order to contribute to our understanding of how CNK2 alterations might cause developmental defects, and we have elucidated a functional role for CNK2 in the molecular processes that govern morphology of the postsynaptic density (PSD). We have also identified novel CNK2 interaction partners and explored their functional interdependency with CNK2. We focussed on the novel interaction partner TRAF2- and NCK-interacting kinase TNIK, which is also associated with ID. Both CNK2 and TNIK are expressed in neuronal dendrites and concentrated in dendritic spines, and staining with synaptic markers indicates a clear postsynaptic localisation. Importantly, our data highlight that CNK2 plays a role in directing TNIK subcellular localisation, and in neurons, CNK2 participates in ensuring that this multifunctional kinase is present in the correct place at desirable levels. In summary, our data indicate that CNK2 expression is critical for modulating PSD morphology; moreover, our study highlights that CNK2 functions as a scaffold with the potential to direct the localisation of regulatory proteins within the cell. Importantly, we describe a novel link between CNK2 and the regulatory kinase TNIK, and provide evidence supporting the idea that alterations in CNK2 localisation and expression have the potential to influence the behaviour of TNIK and other important regulatory molecules in neurons.