DYRK1B regulates Hedgehog-induced microtubule acetylation
DYRK1B regulates Hedgehog-induced microtubule acetylation
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DOI：
10.1007/s00018-018-2942-5
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发表时间：
2019-01-01
影响因子：
8
通讯作者：
Lauth, Matthias
中科院分区：
文献类型：
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作者：
Singh, Rajeev;Holz, Philipp Simon;Lauth, Matthias
微管蛋白亚基的翻译后修饰（PTM）对微管（MT）细胞骨架的生理功能具有重要意义。虽然在鉴定进行MT-PTM的酶方面取得了重大进展，但关于细胞间信号分子及其相关通路如何调节信号接收细胞内的MT-PTM依赖性过程的知识很少。在这里，我们表明，刺猬（Hh）信号，一个典型的细胞间信号系统，影响MT乙酰化状态在哺乳动物细胞。从机制上讲，Hh途径活性增加了MT相关DYRK 1B激酶的水平，导致通过丝氨酸9的磷酸化抑制GSK 3，随后抑制HDAC 6酶活性。由于HDAC 6代表一种主要的微管蛋白脱乙酰酶，其抑制增加乙酰化MT的水平。通过激活DYRK 1B，Hh信号传导促进MT依赖性过程，例如细胞内线粒体转运、间充质细胞极化或定向细胞迁移。两者合计，我们提供的证据表明，通过Hh信号的细胞间通信可以调节MT细胞骨架，并通过影响微管蛋白乙酰化的水平，有助于MT依赖的过程。
The posttranslational modification (PTM) of tubulin subunits is important for the physiological functions of the microtubule (MT) cytoskeleton. Although major advances have been made in the identification of enzymes carrying out MT-PTMs, little knowledge is available on how intercellular signaling molecules and their associated pathways regulate MT-PTM-dependent processes inside signal-receiving cells. Here we show that Hedgehog (Hh) signaling, a paradigmatic intercellular signaling system, affects the MT acetylation state in mammalian cells. Mechanistically, Hh pathway activity increases the levels of the MT-associated DYRK1B kinase, resulting in the inhibition of GSK3 through phosphorylation of Serine 9 and the subsequent suppression of HDAC6 enzyme activity. Since HDAC6 represents a major tubulin deacetylase, its inhibition increases the levels of acetylated MTs. Through the activation of DYRK1B, Hh signaling facilitates MT-dependent processes such as intracellular mitochondrial transport, mesenchymal cell polarization or directed cell migration. Taken together, we provide evidence that intercellular communication through Hh signals can regulate the MT cytoskeleton and contribute to MT-dependent processes by affecting the level of tubulin acetylation.