Lemur tail kinase 1 (LMTK1) regulates the endosomal localization of β-secretase BACE1
Lemur tail kinase 1 (LMTK1) regulates the endosomal localization of β-secretase BACE1
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DOI：
10.1093/jb/mvab094
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发表时间：
2021-09-15
影响因子：
2.7
通讯作者：
Hisanaga, Shin-ichi
中科院分区：
文献类型：
--
作者：
Komaki, Keisuke;Takano, Tetsuya;Hisanaga, Shin-ichi
狐猴尾激酶1（LMTK 1）是一种胞内体丝氨酸/苏氨酸激酶，以前被称为凋亡相关酪氨酸激酶（AATYK）。我们最近报道，LMTK 1通过Rab 11介导的囊泡运输调控轴突生长、树突分枝和棘形成。Rab 11是一种调节循环内体运输的小GTdR，被证明与迟发性阿尔茨海默病（LOAD）有关。事实上，全基因组关联研究确定了许多调节囊泡转运的蛋白质作为LOAD的风险因素。此外，LMTK 1已被报道是额颞叶痴呆的危险因素。然后，我们假设LMTK 1通过囊泡运输促进AD的发展，并研究了LMTK 1对AD相关蛋白、淀粉样前体蛋白（APP）和β-位点APP裂解酶1（BACE 1）的细胞定位的影响。BACE 1对APP的β-切割是A β生成的起始和限速步骤。我们发现，LMTK 1积累BACE 1，但不是APP，核周内体室，而激酶阴性（kn）突变体的LMTK 1A没有。ss-C-末端片段在LMTK 1A kn过表达下倾向于增加。此外，AD脑中LMTK 1A的表达水平降低。这些结果表明LMTK 1通过调节BACE 1的适当内体定位参与AD发展的可能性。
Lemur tail kinase 1 (LMTK1), previously called apoptosis-associated tyrosine kinase (AATYK), is an endosomal Ser/Thr kinase. We recently reported that LMTK1 regulates axon outgrowth, dendrite arborization and spine formation via Rab11-mediated vesicle transport. Rab11, a small GTPase regulating recycling endosome trafficking, is shown to be associated with late-onset Alzheimer's disease (LOAD). In fact, genome-wide association studies identified many proteins regulating vesicle transport as risk factors for LOAD. Furthermore, LMTK1 has been reported to be a risk factor for frontotemporal dementia. Then, we hypothesized that LMTK1 contributes to AD development through vesicle transport and examined the effect of LMTK1 on the cellular localization of AD-related proteins, amyloid precursor protein (APP) and ss-site APP cleaving enzyme 1 (BACE1). The ss-cleavage of APP by BACE1 is the initial and rate-limiting step in A ss generation. We found that LMTK1 accumulated BACE1, but not APP, to the perinuclear endosomal compartment, whereas the kinase-negative(kn) mutant of LMTK1A did not. The ss-C-terminal fragment was prone to increase under overexpression of LMTK1A kn. Moreover, the expression level of LMTK1Awas reduced inADbrains. These results suggest the possibility that LMTK1 is involved in AD development through the regulation of the proper endosomal localization of BACE1.