The EBAX-type Cullin-RING E3 ligase and Hsp90 guard the protein quality of the SAX-3/Robo receptor in developing neurons.
The EBAX-type Cullin-RING E3 ligase and Hsp90 guard the protein quality of the SAX-3/Robo receptor in developing neurons.
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DOI：
10.1016/j.neuron.2013.06.035
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发表时间：
2013-09-04
期刊：
影响因子：
16.2
通讯作者：
Jin Y
中科院分区：
文献类型：
--
作者：
Wang Z;Hou Y;Guo X;van der Voet M;Boxem M;Dixon JE;Chisholm AD;Jin Y
尽管蛋白质质量控制（PQC）通常被认为对神经系统的发育很重要，但神经元PQC的具体机制仍然知之甚少。在这里，我们报道了秀丽隐杆线虫EBAX-1（伸长bc结合轴突调节剂），一个保守的BC-box蛋白，通过SAX-3/Robo受体的PQC调节轴突引导。EBAX-1可以缓冲温度变化带来的制导误差。作为含有长链蛋白bc的Cullin-RING泛素连接酶（CRL）中的一个底物识别亚基，EBAX-1还与细胞质内的Hsp90伴侣DAF-21结合。ebax型CRL和DAF-21协同调节sax -3介导的轴突寻路。生化和影像学分析表明，EBAX-1特异性识别错误折叠的SAX-3，并促进其在体外和体内的降解。重要的是，脊椎动物EBAX也表现出对与水平凝视性麻痹伴进行性脊柱侧凸（HGPPS）有关的异常Robo3的底物偏好。总之，我们的研究结果表明，ebax型CRL和DAF-21/Hsp90介导的分诊PQC机制维持了神经元布线的准确性。
Although protein quality control (PQC) is generally perceived as important for the development of the nervous system, the specific mechanisms of neuronal PQC have remained poorly understood. Here, we report that C. elegans EBAX-1 (Elongin BC-Binding AXon regulator), a conserved BC-box protein, regulates axon guidance through PQC of the SAX-3/Robo receptor. EBAX-1 buffers guidance errors against temperature variations. As a substrate-recognition subunit in the Elongin BC-containing Cullin-RING ubiquitin ligase (CRL), EBAX-1 also binds to DAF-21, a cytosolic Hsp90 chaperone. The EBAX-type CRL and DAF-21 collaboratively regulate SAX-3-mediated axon pathfinding. Biochemical and imaging assays indicate that EBAX-1 specifically recognizes misfolded SAX-3 and promotes its degradation in vitro and in vivo. Importantly, vertebrate EBAX also shows substrate preference towards aberrant Robo3 implicated in horizontal gaze palsy with progressive scoliosis (HGPPS). Together, our findings demonstrate a triage PQC mechanism mediated by the EBAX-type CRL and DAF-21/Hsp90 that maintains the accuracy of neuronal wiring.
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