Axon development is regulated at genetic and proteomic interfaces between the integrin adhesome and the RPM-1 ubiquitin ligase signaling hub.
Axon development is regulated at genetic and proteomic interfaces between the integrin adhesome and the RPM-1 ubiquitin ligase signaling hub.
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轴突发育在整合素粘附体和 RPM-1 泛素连接酶信号中枢之间的遗传和蛋白质组界面上受到调节。
DOI：
10.1101/2023.11.15.566604
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Grill,Brock
中科院分区：
文献类型：
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作者：
Amezquita,Jonathan;Desbois,Muriel;Opperman,KarlaJ;Pak,JosephS;Christensen,ElyseL;Nguyen,NikkiT;Diaz-Garcia,Karen;Borgen,MelissaA;Grill,Brock
整合素信号转导在发育和疾病中起重要作用。整合素粘附体是一种粘附信号网络，主要是利用生物信息学和蛋白质组学来定义的。到目前为止，还没有使用整合的蛋白质组学和遗传学方法研究粘附体。在这里，蛋白质组学研究在C。elegans鉴定了RPM-1遍在蛋白连接酶信号中枢和包括Talin、Kindlin和β-整联蛋白在内的许多粘附体组分之间的物理关联。C.秀丽线虫RPM-1与人MYCBP 2同源，MYCBP 2是与神经发育障碍相关的神经系统发育中的重要参与者。使用神经元特异性CRISPR功能丧失策略，我们表明核心粘附体成分影响轴突发育并与RPM-1发生遗传相互作用。从机制上讲，塔林反对RPM-1在一个功能性的“拔河”生长锥，这是需要准确的轴突终止。因此，我们的研究结果通过多组分遗传和物理界面与关键的神经元信号传导枢纽正交验证了粘附体，并确定了粘附体与大脑疾病之间的新联系。
Integrin signaling plays important roles in development and disease. An adhesion signaling network called the integrin adhesome has been principally defined using bioinformatics and proteomics. To date, the adhesome has not been studied using integrated proteomic and genetic approaches. Here, proteomic studies in C. elegans identified physical associations between the RPM-1 ubiquitin ligase signaling hub and numerous adhesome components including Talin, Kindlin and beta-integrin. C. elegans RPM-1 is orthologous to human MYCBP2, a prominent player in nervous system development associated with a neurodevelopmental disorder. Using neuron-specific, CRISPR loss-of-function strategies, we show that core adhesome components affect axon development and interact genetically with RPM-1. Mechanistically, Talin opposes RPM-1 in a functional ‘tug-of-war’ on growth cones that is required for accurate axon termination. Thus, our findings orthogonally validate the adhesome via multi-component genetic and physical interfaces with a key neuronal signaling hub and identify new links between the adhesome and brain disorders.