Α-tubulin K40 acetylation is required for contact inhibition of proliferation and cell-substrate adhesion.
Α-tubulin K40 acetylation is required for contact inhibition of proliferation and cell-substrate adhesion.
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DOI：
10.1091/mbc.e13-10-0609
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发表时间：
2014-06-15
影响因子：
3.3
通讯作者：
Nachury MV
中科院分区：
文献类型：
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作者：
Aguilar A;Becker L;Tedeschi T;Heller S;Iomini C;Nachury MV
α-微管蛋白在赖氨酸40上的乙酰化是微管长寿的标志，但其功能尚不清楚。敲除微管蛋白乙酰转移酶αTAT1表明，α-微管蛋白K40乙酰化是接触性抑制细胞增殖的关键。有人认为乙酰化的微管促进了河马调节剂Merlin的运输。α-微管蛋白在赖氨酸40上的乙酰化标志着轴突和纤毛等结构中微管的长寿命，然而α-微管蛋白K40乙酰化的生理作用尚不清楚。虽然小鼠α-微管蛋白K40乙酰转移酶αTat1的遗传消融没有在发育中的动物中产生可检测到的表型，但在培养的αTat1−/−成纤维细胞中，接触抑制增殖和细胞-基质黏附显著受损。首先，α-Tat-1−/−成纤维细胞在融合单层阶段后继续增殖。与之一致的是，αTat1−/−细胞未能激活河马信号以响应细胞密度的增加，河马调节因子Merlin的微管联系被破坏。其次，αTat1−/−细胞含有极少的局灶性粘连，其附着生长表面的能力大大受损。尽管αTAT1的催化活性对于单层的形成是不必要的，但在细胞密度增加的情况下，它是细胞黏附和抑制细胞增殖和激活HIPPO途径所必需的。由于α-微管蛋白K40乙酰化在很大程度上被αTAT1缺失消除，我们认为乙酰化微管通过河马途径调节接触抑制增殖。
Acetylation of α-tubulin on lysine 40 is a mark of long-lived microtubules, but its function is elusive. Knocking out the tubulin acetyltransferase αTAT1 shows that α-tubulin K40 acetylation is critical for contact inhibition of proliferation. It is proposed that acetylated microtubules facilitate transport of the Hippo regulator Merlin. Acetylation of α-tubulin on lysine 40 marks long-lived microtubules in structures such as axons and cilia, and yet the physiological role of α-tubulin K40 acetylation is elusive. Although genetic ablation of the α-tubulin K40 acetyltransferase αTat1 in mice did not lead to detectable phenotypes in the developing animals, contact inhibition of proliferation and cell–substrate adhesion were significantly compromised in cultured αTat1−/− fibroblasts. First, αTat1−/− fibroblasts kept proliferating beyond the confluent monolayer stage. Congruently, αTat1−/− cells failed to activate Hippo signaling in response to increased cell density, and the microtubule association of the Hippo regulator Merlin was disrupted. Second, αTat1−/− cells contained very few focal adhesions, and their ability to adhere to growth surfaces was greatly impaired. Whereas the catalytic activity of αTAT1 was dispensable for monolayer formation, it was necessary for cell adhesion and restrained cell proliferation and activation of the Hippo pathway at elevated cell density. Because α-tubulin K40 acetylation is largely eliminated by deletion of αTAT1, we propose that acetylated microtubules regulate contact inhibition of proliferation through the Hippo pathway.