The cytoplasmic tail of rhodopsin triggers rapid rod degeneration in kinesin-2 mutants
The cytoplasmic tail of rhodopsin triggers rapid rod degeneration in kinesin-2 mutants
复制标题
视紫红质的细胞质尾部引发驱动蛋白-2突变体的快速视杆变性
DOI：
10.1074/jbc.m117.784017
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发表时间：
2017-10-20
影响因子：
4.8
通讯作者：
Zhao, Chengtian
中科院分区：
文献类型：
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作者：
Feng, Dong;Chen, Zhe;Zhao, Chengtian
光感受器变性可导致失明，是世界上最常见的神经退行性疾病。虽然许多基因参与光感受器变性已被确定，潜在的机制仍有待阐明。在这里，我们研究了斑马鱼kif3a和kif3b突变体的光感受器发育，它们影响激酶2复合物的两个亚基。在这两种突变体中，杆状细胞迅速退化，而锥状细胞则经历了缓慢的退化过程。值得注意的是，kif3a突变体的光感受器缺陷比kif3b突变体严重得多。在kif3a突变体的锥体光感受器中，视蛋白在顶端区域积累，形成异常的膜结构。相反，视紫红质在杆状细胞体膜中富集，这是这些突变体中杆状细胞快速变性的主要原因。此外，在kif3a和kif3b突变体中，去除视紫红质的细胞质尾部以降低其功能，但并未降低视紫红质的表达水平，从而阻止了杆状变性。值得注意的是，在kif3a突变体中，全长视紫红质或其胞质尾部区域的过表达，而缺乏胞质尾部区域的视紫红质不表达，会加剧杆状体变性，这意味着胞质尾部在杆状体变性中起重要作用。最后，我们发现视紫红质的胞质尾部可能通过激活下游钙信号通路来触发杆状细胞变性，因为在kif3a突变体中，细胞内钙释放抑制剂的药物治疗可以阻止杆状细胞变性。我们的研究结果表明，在视蛋白引发的光感受器变性过程中，视紫红质细胞质结构域具有以前未知的功能，并可能为治疗这种疾病开辟新的途径。
Photoreceptor degeneration can lead to blindness and represents the most common form of neural degenerative disease worldwide. Although many genes involved in photoreceptor degeneration have been identified, the underlying mechanisms remain to be elucidated. Here we examined photoreceptor development in zebrafish kif3a and kif3b mutants, which affect two subunits of the kinesin-2 complex. In both mutants, rods degenerated quickly, whereas cones underwent a slow degeneration process. Notably, the photoreceptor defects were considerably more severe in kif3a mutants than in kif3b mutants. In the cone photoreceptors of kif3a mutants, opsin proteins accumulated in the apical region and formed abnormal membrane structures. In contrast, rhodopsins were enriched in the rod cell body membrane and represented the primary reason for rapid rod degeneration in these mutants. Moreover, removal of the cytoplasmic tail of rhodopsin to reduce its function, but not decreasing rhodopsin expression levels, prevented rod degeneration in both kif3a and kif3b mutants. Of note, overexpression of full-length rhodopsin or its cytoplasmic tail domain, but not of rhodopsin lacking the cytoplasmic tail, exacerbated rod degeneration in kif3a mutants, implying an important role of the cytoplasmic tail in rod degeneration. Finally, we showed that the cytoplasmic tail of rhodopsin might trigger rod degeneration through activating the downstream calcium signaling pathway, as drug treatment with inhibitors of intracellular calcium release prevented rod degeneration in kif3a mutants. Our results demonstrate a previously unknown function of the rhodopsin cytoplasmic domain during opsin-triggered photoreceptor degeneration and may open up new avenues for managing this disease.