NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
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DOI：
10.1073/pnas.1718336115
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发表时间：
2018-04-24
影响因子：
11.1
通讯作者：
Arnesen T
中科院分区：
文献类型：
--
作者：
Drazic A;Aksnes H;Marie M;Boczkowska M;Varland S;Timmerman E;Foyn H;Glomnes N;Rebowski G;Impens F;Gevaert K;Dominguez R;Arnesen T
超过80%的人类蛋白质在翻译过程中是N-末端（Nt）-乙酰化的。相比之下，肌动蛋白，最丰富的蛋白质在细胞质中的动物细胞，是NT-乙酰化postperturbationally和以下的一个独特的多步骤的机制，一直没有得到很好的表征。在这里，我们描述了肌动蛋白的N-末端乙酰转移酶（NAT），NAA 80的发现。我们进一步证明，肌动蛋白NT-乙酰化在细丝组装，细胞骨架组织和细胞运动中起着至关重要的作用，导致单体丝状肌动蛋白和较少的板状伪足和丝状伪足的比例净增加。这些作用集中在减少细胞运动过度上。这项工作建立了NT-乙酰化的作用，在动物中最丰富的细胞骨架蛋白，并揭示了NAT的作用postperfectationally和一个单一的专用基板。肌动蛋白是自然界中最丰富的蛋白质之一，参与了无数的细胞功能，从细胞器运输和病原体运动到细胞迁移和基因转录调控。肌动蛋白的细胞活性取决于其单体和丝状形式之间的动态转变，这是一个在细胞中由大量肌动蛋白结合和信号蛋白精细调控的过程。此外，一些翻译后修饰控制肌动蛋白的细胞功能，包括最显着的N-末端（Nt）-乙酰化，在整个动物界普遍的修饰。然而，肌动蛋白N-末端乙酰化的生物学作用和机制知之甚少，肌动蛋白的N-末端乙酰转移酶（NAT）的身份仍然是一个谜。在这里，我们发现，NAA 80，建议NAT酶的底物特异性还没有得到表征，是NT-乙酰化肌动蛋白。我们进一步表明，肌动蛋白NT-乙酰化起着至关重要的作用，在细胞骨架组装在体外和细胞。NT-乙酰化的情况下导致肌动蛋白丝解聚和伸长的速率显着差异，包括由formin驱动的伸长，而Arp 2/3复合物的丝成核大多不受影响。NAA 80基因敲除的细胞显示出严重改变的细胞骨架组织，包括丝状肌动蛋白与球状肌动蛋白的比例增加，丝状伪足和片状伪足形成增加，以及细胞运动加速。总之，这些结果证明了NAA 80作为肌动蛋白NAT的作用，并揭示了肌动蛋白NT-乙酰化在控制细胞骨架结构和动力学中的关键作用。
More than 80% of human proteins are N-terminal (Nt)–acetylated during translation. In contrast, actin, the most abundant protein in the cytoplasm of animal cells, is Nt-acetylated posttranslationally and following a unique multistep mechanism that has remained poorly characterized. Here, we describe the discovery of actin’s N-terminal acetyltransferase (NAT), NAA80. We further demonstrate that actin Nt-acetylation plays essential roles in filament assembly, cytoskeleton organization, and cell motility, resulting in a net increase in the ratio of monomeric to filamentous actin and fewer lamellipodia and filopodia. These effects converge to reduce cell hypermotility. This work establishes the role of Nt-acetylation for the most abundant cytoskeletal protein in animals and reveals a NAT acting posttranslationally and on a single dedicated substrate. Actin, one of the most abundant proteins in nature, participates in countless cellular functions ranging from organelle trafficking and pathogen motility to cell migration and regulation of gene transcription. Actin’s cellular activities depend on the dynamic transition between its monomeric and filamentous forms, a process exquisitely regulated in cells by a large number of actin-binding and signaling proteins. Additionally, several posttranslational modifications control the cellular functions of actin, including most notably N-terminal (Nt)-acetylation, a prevalent modification throughout the animal kingdom. However, the biological role and mechanism of actin Nt-acetylation are poorly understood, and the identity of actin’s N-terminal acetyltransferase (NAT) has remained a mystery. Here, we reveal that NAA80, a suggested NAT enzyme whose substrate specificity had not been characterized, is Nt-acetylating actin. We further show that actin Nt-acetylation plays crucial roles in cytoskeletal assembly in vitro and in cells. The absence of Nt-acetylation leads to significant differences in the rates of actin filament depolymerization and elongation, including elongation driven by formins, whereas filament nucleation by the Arp2/3 complex is mostly unaffected. NAA80-knockout cells display severely altered cytoskeletal organization, including an increase in the ratio of filamentous to globular actin, increased filopodia and lamellipodia formation, and accelerated cell motility. Together, the results demonstrate NAA80’s role as actin’s NAT and reveal a crucial role for actin Nt-acetylation in the control of cytoskeleton structure and dynamics.
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影响因子：
7
作者：
Bienvenut, Willy V.;Sumpton, David;Giglione, Carmela
通讯作者：
Giglione, Carmela
DOI：
10.1073/pnas.0901931106
发表时间：
2009-05-19
影响因子：
11.1
作者：
Arnesen, Thomas;Van Damme, Petra;Gevaert, Kris
通讯作者：
Gevaert, Kris
DOI：
10.1126/science.1183147
发表时间：
2010-02-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hwang CS;Shemorry A;Varshavsky A
通讯作者：
Varshavsky A
影响因子：
4.8
作者：
Harris, Elizabeth S.;Rouiller, Isabelle;Higgs, Henry N.
通讯作者：
Higgs, Henry N.
DOI：
10.1073/pnas.1719251115
发表时间：
2018-04-24
影响因子：
11.1
作者：
Goris, Marianne;Magin, Robert S.;Arnesen, Thomas
通讯作者：
Arnesen, Thomas