Tumor suppressor KIF1Bβ regulates mitochondrial apoptosis in collaboration with YME1L1
Tumor suppressor KIF1Bβ regulates mitochondrial apoptosis in collaboration with YME1L1
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DOI：
10.1002/mc.22997
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发表时间：
2019-07-01
影响因子：
4.6
通讯作者：
Nakagawara, Akira
中科院分区：
文献类型：
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作者：
Ando, Koji;Yokochi, Tomoki;Nakagawara, Akira
KIF1B beta 是运动蛋白驱动蛋白超家族的成员，是映射到染色体 1p36.2 的单倍体不足肿瘤抑制因子，该染色体在神经嵴衍生肿瘤（包括神经母细胞瘤和嗜铬细胞瘤）中经常被删除。虽然 KIF1B beta 作用于神经生长因子 (NGF) 通路下游以诱导细胞凋亡，但该基因产物的进一步分子功能在很大程度上尚未被探索。在这项研究中，我们报告 KIF1B beta 会破坏线粒体形态结构的稳定性，而线粒体形态结构对于细胞存活和凋亡至关重要。我们确定了 YME1L1（一种负责线粒体 GTP 酶 OPA1 裂解的线粒体金属蛋白酶）作为 KIF1B beta 的物理相互作用伙伴。 KIF1B beta 通过其死亡诱导区与 YME1L1 相互作用，启动 YME1L1 的蛋白酶活性来裂解 OPA1 的长形式，从而导致线粒体断裂。 YME1L1 的过表达促进细胞凋亡，而 YME1L1 的敲低则促进细胞生长。 YME1L1 高表达与神经母细胞瘤更好的预后显着相关。此外，在 NGF 缺失的 PC12 细胞中，KIF1B beta 和 YME1L1 表达上调，并伴有线粒体断裂和细胞凋亡。然而，小干扰RNA介导的单独敲低任一蛋白质，显着抑制了NGF耗竭诱导的细胞凋亡。我们的研究结果表明，肿瘤抑制因子 KIF1B beta 通过与 YME1L1 协同调节线粒体的结构和功能动态，在线粒体内在介导的细胞凋亡中发挥重要作用。 KIF1B beta/YME1L1/OPA1机制的功能障碍可能与神经嵴源性肿瘤的恶性生物学特征以及神经退行性疾病的发生和进展有关。
KIF1B beta, a member of the kinesin superfamily of motor proteins, is a haploinsufficient tumor suppressor mapped to chromosome 1p36.2, which is frequently deleted in neural crest-derived tumors, including neuroblastoma and pheochromocytoma. While KIF1B beta acts downstream of the nerve growth factor (NGF) pathway to induce apoptosis, further molecular functions of this gene product have largely been unexplored. In this study, we report that KIF1B beta destabilizes the morphological structure of mitochondria, which is critical for cell survival and apoptosis. We identified YME1L1, a mitochondrial metalloprotease responsible for the cleavage of the mitochondrial GTPase OPA1, as a physical interacting partner of KIF1B beta. KIF1B beta interacted with YME1L1 through its death-inducing region, as initiated the protease activity of YME1L1 to cleave the long forms of OPA1, resulting in mitochondrial fragmentation. Overexpression of YME1L1 promoted apoptosis, while knockdown of YME1L1 promoted cell growth. High YME1L1 expression was significantly associated with a better prognosis in neuroblastoma. Furthermore, in NGF-deprived PC12 cells, KIF1B beta and YME1L1 were upregulated, accompanied by mitochondrial fragmentation and apoptotic cell death. Small interfering RNA-mediated knockdown of either protein alone, however, remarkably inhibited the NGF depletion-induced apoptosis. Our findings indicate that tumor suppressor KIF1B beta plays an important role in intrinsic mitochondria-mediated apoptosis through the regulation of structural and functional dynamics of mitochondria in collaboration with YME1L1. Dysfunction of the KIF1B beta/YME1L1/OPA1 mechanism may be involved in malignant biological features of neural crest-derived tumors as well as the initiation and progression of neurodegenerative diseases.