Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Neuron. 2013 Sep 4;79(5):903-16. doi: 10.1016/j.neuron.2013.06.035.
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 Elongin BC-binding axon regulator (EBAX-1), 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 toward 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.
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 的具体机制仍知之甚少。在这里，我们报告说，秀丽隐杆线虫的 Elongin BC 结合轴突调节因子 (EBAX-1)，一种保守的 BC 盒蛋白，通过 SAX-3/Robo 受体的 PQC 来调节轴突导向。EBAX-1 缓冲了温度变化对导向错误的影响。作为含有 Elongin BC 的 Cullin-RING 泛素连接酶 (CRL) 中的底物识别亚基，EBAX-1 还与细胞质 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。生化和成像分析表明，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 还显示出对水平凝视麻痹伴进行性脊柱侧凸 (HGPPS) 中涉及的异常 Robo3 的底物偏好。总之，我们的发现表明，EBAX 型 CRL 和 DAF-21/Hsp90 介导的分类 PQC 机制可维持神经元连接的准确性。
