5月14日,，中國科學(xué)院北京基因組研究所疾病基因組與個體化醫(yī)療實驗室“百人計劃”研究員楊運桂研究組,，與奧斯陸大學(xué)Arne Klungland教授合作完成的“ALKBH4依賴的肌動蛋白去甲基化調(diào)控胞質(zhì)分裂機制研究”取得重要進展，相關(guān)學(xué)術(shù)論文在Nature子刊《自然·通訊》(Nature Communications)雜志以“ALKBH4 - dependent demethylation of actin regulates actomyosin dynamics”為題在線發(fā)表,。該研究闡明了一種新的細胞胞質(zhì)分裂機制,，ALKBH4作為新的肌動球蛋白（Actomyosin）調(diào)控因子被發(fā)現(xiàn)。
胞質(zhì)分裂需要以肌動球蛋白（由微絲F-actin）和非肌肉II型肌球蛋白（Non-muscle Myosin II,， NM II）組成）為核心組分的收縮環(huán)在分裂溝處收縮來提供動力,，將一個母細胞分裂成兩個子細胞。在胞質(zhì)分裂過程中,，分裂溝和分裂平面的確定需要微管和微絲協(xié)同進行信息傳遞,，最終引起肌動球蛋白組裝形成收縮環(huán)。收縮環(huán)是一種動態(tài)的細胞器,，隨著F-actin（由肌動蛋白actin聚合而成）和NM II變化而變化,，并決定著母細胞能否成功分裂。NM II是胞質(zhì)分裂過程中收縮環(huán)上主要的動力蛋白,，它在微絲上的移動和F-actin解聚都是分裂溝收縮所必需的,。分裂溝收縮依賴于收縮環(huán)中肌動球蛋白產(chǎn)生的動力，但是肌動球蛋白收縮的具體機制現(xiàn)在還不清楚,，尤其是肌動蛋白的翻譯后修飾是如何調(diào)控肌動球蛋白的動態(tài)過程也是未知的,。
本研究證明了ALKBH4蛋白可以介導(dǎo)肌動蛋白上一種新的84位賴氨酸單甲基化（actin K84me1）的去甲基化。肌動蛋白的甲基化和去甲基化調(diào)控肌動球蛋白間的相互作用及生物學(xué)功能,，包括胞質(zhì)分裂和細胞遷移,。ALKBH4依賴的肌動蛋白去甲基化通過促進肌動球蛋白相互作用調(diào)控其收縮功能，ALKBH4通過與肌動蛋白K84me1相互作用被募集到收縮環(huán)和中體上,，并將肌動蛋白K84me1去甲基化,，為NM II創(chuàng)造結(jié)合肌動蛋白的位點。肌動蛋白去甲基化使得NM II能沿著F-actin動態(tài)的滑動,，并產(chǎn)生收縮力促進收縮環(huán)收縮,，使分裂溝內(nèi)陷完成胞質(zhì)分裂。
該項工作得到了中國科學(xué)院,、科技部,、國家自然科學(xué)基金委及教育部經(jīng)費資助。（生物谷Bioon.com）
doi:10.1038/ncomms2863
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ALKBH4-dependent demethylation of actin regulates actomyosin dynamics
Ming-Ming Li, Anja Nilsen, Yue Shi, Markus Fusser, Yue-He Ding, Ye Fu, Bo Liu, Yamei Niu, Yong-Sheng Wu, Chun-Min Huang, Maria Olofsson, Kang-Xuan Jin, Ying Lv, Xing-Zhi Xu, Chuan He, Meng-Qiu Dong, Jannie M. Rendtlew Danielsen, Arne Klungland & Yun-Gui Yang
Regulation of actomyosin dynamics by post-transcriptional modifications in cytoplasmic actin is still poorly understood. Here we demonstrate that dioxygenase ALKBH4-mediated demethylation of a monomethylated site in actin (K84me1) regulates actin–myosin interaction and actomyosin-dependent processes such as cytokinesis and cell migration. ALKBH4-deficient cells display elevated K84me1 levels. Non-muscle myosin II only interacts with unmethylated actin and its proper recruitment to and interaction with actin depend on ALKBH4. ALKBH4 co-localizes with the actomyosin-based contractile ring and midbody via association with methylated actin. ALKBH4-mediated regulation of actomyosin dynamics is completely dependent on its catalytic activity. Disorganization of cleavage furrow components and multinucleation associated with ALKBH4 deficiency can all be restored by reconstitution with wild-type but not catalytically inactive ALKBH4. Similar to actin and myosin knock-out mice, homozygous Alkbh4 mutant mice display early embryonic lethality. These findings imply that ALKBH4-dependent actin demethylation regulates actomyosin function by promoting actin-non-muscle myosin II interactio
