Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export
Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export
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DOI：
10.15252/embj.201487807
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发表时间：
2014-10-16
期刊：
影响因子：
11.4
通讯作者：
Cai, Huaibin
中科院分区：
文献类型：
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作者：
Cho, Hyun Jin;Yu, Jia;Cai, Huaibin
富含亮氨酸的重复蛋白2(LRRK2)与帕金森氏病(PD)和其他疾病有关。然而，它的正常生理功能和致病特性仍然难以捉摸。在这里，我们证明了LRRK2通过在内质网出口部位(ERES)锚定Sec16A来调节ER-高尔基体的顺行运输。LRRK2与ERES形成过程中的关键蛋白Sec16A相互作用，共定位。LRRK2缺失导致Sec16A从ERES中分散，并损害内质网输出。在神经元中，LRRK2和Sec16A在树突状ERES(DERES)上显示了广泛的共同定位，DERE局部调节蛋白质到树突棘的运输。LRRK2的缺失影响了Sec16A与DERES的结合，并损害了谷氨酸受体在细胞/突触表面的活性依赖性靶向。此外，PD相关的LRRK2 R1441C错义突变干扰了LRRK2与Sec16A的相互作用，也影响了ER-Golgi转运，而这些功能并不需要LRRK2的活性。因此，我们的发现揭示了LRRK2在内质网高尔基体转运中的新的生理功能，提示ERES功能障碍可能参与了帕金森病的发病。
Leucine-rich repeat kinase 2 (LRRK2) has been associated with Parkinson's disease (PD) and other disorders. However, its normal physiological functions and pathogenic properties remain elusive. Here we show that LRRK2 regulates the anterograde ER-Golgi transport through anchoring Sec16A at the endoplasmic reticulum exit sites (ERES). LRRK2 interacted and co-localized with Sec16A, a key protein in the formation of ERES. Lrrk2 depletion caused a dispersion of Sec16A from ERES and impaired ER export. In neurons, LRRK2 and Sec16A showed extensive co-localization at the dendritic ERES (dERES) that locally regulate the transport of proteins to the dendritic spines. A loss of Lrrk2 affected the association of Sec16A with dERES and impaired the activity-dependent targeting of glutamate receptors onto the cell/synapse surface. Furthermore, the PD-related LRRK2 R1441C missense mutation in the GTPase domain interfered with the interaction of LRRK2 with Sec16A and also affected ER-Golgi transport, while LRRK2 kinase activity was not required for these functions. Therefore, our findings reveal a new physiological function of LRRK2 in ER-Golgi transport, suggesting ERES dysfunction may contribute to the pathogenesis of PD.