Mdm20 Modulates Actin Remodeling through the mTORC2 Pathway via Its Effect on Rictor Expression.
Mdm20 Modulates Actin Remodeling through the mTORC2 Pathway via Its Effect on Rictor Expression.
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DOI：
10.1371/journal.pone.0142943
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Mori N
中科院分区：
文献类型：
--
作者：
Yasuda K;Takahashi M;Mori N
NatB是一种n端乙酰转移酶，由催化Nat5亚基和辅助Mdm20亚基组成。在酵母中，NatB在蛋白质从头合成过程中使蛋白质的n端蛋氨酸乙酰化，并通过原肌球蛋白（Trpm）的n端乙酰化调节肌动蛋白重塑，通过与肌动蛋白相互作用稳定肌动蛋白细胞骨架。然而，在哺乳动物细胞中，Mdm20和Nat5亚基的生物学功能尚不清楚。在本研究中，我们首次发现mdm20敲低（KD），而不是Nat5-KD，在HEK293和HeLa细胞中不仅抑制细胞生长，而且抑制细胞运动。虽然应激纤维在Mdm20-KD细胞中形成，而在对照细胞或Nat5-KD细胞中没有形成，但Trpm的定位与Mdm20-KD细胞中应激纤维的形成并不一致。值得注意的是，Mdm20的敲低通过翻译后调控降低了mTORC2复合物组分Rictor的表达。此外，在Mdm20-KD细胞中，调节肌动蛋白骨架组织的PKCαS657磷酸化也减少。我们的数据还表明，FoxO1磷酸化受Mdm20-mTORC2-Akt通路调控，以响应血清饥饿和胰岛素刺激。综上所述，本研究结果表明，Mdm20作为一种新的Rictor调节因子，从而控制mTORC2活性，并导致PKCαS657和fox01的激活。
NatB is an N-terminal acetyltransferase consisting of a catalytic Nat5 subunit and an auxiliary Mdm20 subunit. In yeast, NatB acetylates N-terminal methionines of proteins during de novo protein synthesis and also regulates actin remodeling through N-terminal acetylation of tropomyosin (Trpm), which stabilizes the actin cytoskeleton by interacting with actin. However, in mammalian cells, the biological functions of the Mdm20 and Nat5 subunits are not well understood. In the present study, we show for the first time that Mdm20-knockdown (KD), but not Nat5-KD, in HEK293 and HeLa cells suppresses not only cell growth, but also cellular motility. Although stress fibers were formed in Mdm20-KD cells, and not in control or Nat5-KD cells, the localization of Trpm did not coincide with the formation of stress fibers in Mdm20-KD cells. Notably, knockdown of Mdm20 reduced the expression of Rictor, an mTORC2 complex component, through post-translational regulation. Additionally, PKCαS657 phosphorylation, which regulates the organization of the actin cytoskeleton, was also reduced in Mdm20-KD cells. Our data also suggest that FoxO1 phosphorylation is regulated by the Mdm20-mTORC2-Akt pathway in response to serum starvation and insulin stimulation. Taken together, the present findings suggest that Mdm20 acts as a novel regulator of Rictor, thereby controlling mTORC2 activity, and leading to the activation of PKCαS657 and FoxO1.