An actin filament branching surveillance system regulates cell cycle progression, cytokinesis and primary ciliogenesis.
An actin filament branching surveillance system regulates cell cycle progression, cytokinesis and primary ciliogenesis.
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DOI：
10.1038/s41467-023-37340-z
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发表时间：
2023-03-27
影响因子：
16.6
通讯作者：
Zhong, Qing
中科院分区：
文献类型：
--
作者：
Cao, Muqing;Zou, Xiaoxiao;Li, Chaoyi;Lin, Zaisheng;Wang, Ni;Zou, Zhongju;Ye, Youqiong;Seemann, Joachim;Levine, Beth;Tang, Zaiming;Zhong, Qing
细胞周期控制功能障碍和原发性纤毛发生缺陷是许多癌症的两个特征。这些事件是否相互关联以及协调它们的驱动机制仍然难以捉摸。在这里，我们确定了一个肌动蛋白丝分支监视系统，提醒细胞的肌动蛋白分支不足，并调节细胞周期的进展，胞质分裂和初级纤毛发生。我们发现口面指综合征1作为II类成核促进因子促进Arp 2/3复合物介导的肌动蛋白分支。肌动蛋白分支的扰动通过液体到凝胶的转变促进OFD 1的降解和失活。OFD 1的消除或OFD 1-Arp 2/3相互作用的破坏通过RB依赖性机制驱动增殖的非转化细胞进入纤毛发生的静止状态，而它通过肌动球蛋白环畸形导致癌基因转化的细胞/癌细胞不完全的胞质分裂和不可逆的有丝分裂灾难。OFD 1的抑制导致小鼠异种移植模型中多种癌细胞生长的抑制。因此，靶向OFD 1介导的肌动蛋白丝分支监视系统为癌症治疗提供了方向。作者发现，纤毛病变相关蛋白Oral-Facial-Digital syndrome 1作为II类成核促进因子发挥作用，以驱动细胞周期进程所需的肌动蛋白丝分支。干扰这种功能会抑制癌细胞的生长。
Dysfunction of cell cycle control and defects of primary ciliogenesis are two features of many cancers. Whether these events are interconnected and the driving mechanism coordinating them remains elusive. Here, we identify an actin filament branching surveillance system that alerts cells of actin branching insufficiency and regulates cell cycle progression, cytokinesis and primary ciliogenesis. We find that Oral-Facial-Digital syndrome 1 functions as a class II Nucleation promoting factor to promote Arp2/3 complex-mediated actin branching. Perturbation of actin branching promotes OFD1 degradation and inactivation via liquid-to-gel transition. Elimination of OFD1 or disruption of OFD1-Arp2/3 interaction drives proliferating, non-transformed cells into quiescence with ciliogenesis by an RB-dependent mechanism, while it leads oncogene-transformed/cancer cells to incomplete cytokinesis and irreversible mitotic catastrophe via actomyosin ring malformation. Inhibition of OFD1 leads to suppression of multiple cancer cell growth in mouse xenograft models. Thus, targeting OFD1-mediated actin filament branching surveillance system provides a direction for cancer therapy. The authors find that the ciliopathy-associated protein Oral-Facial-Digital syndrome 1 functions as a class II nucleation promoting factor to drive actin filament branching, required for cell cycle progression. Interferring with this function suppresses cancer cell growth.
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影响因子：
3.7
作者：
Hassounah NB;Nagle R;Saboda K;Roe DJ;Dalkin BL;McDermott KM
通讯作者：
McDermott KM
影响因子：
3.3
作者：
Chan FY;Silva AM;Saramago J;Pereira-Sousa J;Brighton HE;Pereira M;Oegema K;Gassmann R;Carvalho AX
通讯作者：
Carvalho AX
影响因子：
7.7
作者：
Helgeson LA;Nolen BJ
通讯作者：
Nolen BJ
影响因子：
7.7
作者：
Kodani A;Yu TW;Johnson JR;Jayaraman D;Johnson TL;Al-Gazali L;Sztriha L;Partlow JN;Kim H;Krup AL;Dammermann A;Krogan NJ;Walsh CA;Reiter JF
通讯作者：
Reiter JF
影响因子：
4.8
作者：
Helgeson, Luke A.;Prendergast, Julianna G.;Nolen, Brad J.
通讯作者：
Nolen, Brad J.