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首页> 外文期刊>Biology Open >Rab35 promotes the recruitment of Rab8, Rab13 and Rab36 to recycling endosomes through MICAL-L1 during neurite outgrowth
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Rab35 promotes the recruitment of Rab8, Rab13 and Rab36 to recycling endosomes through MICAL-L1 during neurite outgrowth

机译：Rab35促进募集Rab8，Rab13和Rab36，以在神经突增生期间通过MICAL-L1回收内体。

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Small GTPase Rab35 is an important molecular switch for endocytic recycling that regulates various cellular processes, including cytokinesis, cell migration, and neurite outgrowth. We previously showed that active Rab35 promotes nerve growth factor (NGF)-induced neurite outgrowth of PC12 cells by recruiting MICAL-L1, a multiple Rab-binding protein, to Arf6-positive recycling endosomes. However, the physiological significance of the multiple Rab-binding ability of MICAL-L1 during neurite outgrowth remained completely unknown. Here we report that Rab35 and MICAL-L1 promote the recruitment of Rab8, Rab13, and Rab36 to Arf6-positive recycling endosomes during neurite outgrowth. We found that Rab35 functions as a master Rab that determines the intracellular localization of MICAL-L1, which in turn functions as a scaffold for Rab8, Rab13, and Rab36. We further showed by functional ablation experiments that each of these downstream Rabs regulates neurite outgrowth in a non-redundant manner downstream of Rab35 and MICAL-L1, e.g. by showing that knockdown of Rab36 inhibited recruitment of Rab36-specific effector JIP4 to Arf6-positive recycling endosomes, and caused inhibition of neurite outgrowth without affecting accumulation of Rab8 and Rab13 in the same Arf6-positive area. Our findings suggest the existence of a novel mechanism that recruits multiple Rab proteins at the Arf6-positive compartment by MICAL-L1.
机译：小型GTPase Rab35是内吞再循环的重要分子开关，可调节各种细胞过程，包括胞质分裂，细胞迁移和神经突生长。我们先前显示，活性Rab35通过募集多重Rab结合蛋白MICAL-L1至Arf6阳性的循环内体来促进神经生长因子（NGF）诱导的PC12细胞神经突生长。但是，在神经突生长过程中，MICAL-L1的多重Rab结合能力的生理意义仍然完全未知。在这里我们报告说，Rab35和MICAL-L1在神经突生长过程中促进Rab8，Rab13和Rab36向Arf6阳性回收内体的募集。我们发现Rab35充当主要的Rab，它决定了MICAL-L1在细胞内的定位，而MICAL-L1则充当了Rab8，Rab13和Rab36的支架。我们通过功能性烧蚀实验进一步表明，这些下游Rabs均以非冗余方式在Rab35和MICAL-L1的下游（例如，Rabs）调节神经突的生长。通过显示敲低Rab36抑制Rab36特异性效应子JIP4向Arf6阳性循环内体的募集，并引起神经突生长抑制，而不影响Rab8和Rab13在同一Arf6阳性区域中的积累。我们的发现表明存在一种新的机制，该机制可通过MICAL-L1在Arf6阳性区室募集多个Rab蛋白。

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