Resistance to inhibitors of cholinesterase (Ric)-8A and Gαi contribute to cytokinesis abscission by controlling vacuolar protein-sorting (Vps)34 activity.
Resistance to inhibitors of cholinesterase (Ric)-8A and Gαi contribute to cytokinesis abscission by controlling vacuolar protein-sorting (Vps)34 activity.
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DOI：
10.1371/journal.pone.0086680
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kehrl JH
中科院分区：
文献类型：
--
作者：
Boularan C;Kamenyeva O;Cho H;Kehrl JH
对胆碱酯酶抑制剂（Ric）-8A的抗性是Gαi、Gαq和Gα12/13的鸟嘌呤核苷酸交换因子，其涉及细胞信号传导，并作为新生Gα亚基与细胞膜初始缔合所需的分子伴侣。Ric-8A、Gαi亚基和它们的调节子在分裂前定位于中间体，并与细胞分裂的最后阶段相关联。在这里，我们确定了Ric-8A通过控制Vps 34活性影响胞质分裂和胞质分裂的分子机制。我们发现，Ric-8A蛋白的表达是转录后控制在细胞周期中达到其最高水平在有丝分裂。为了通过FLIM（荧光寿命成像显微镜）测量Ric-8A的构象变化而创建的FRET生物传感器显示Ric-8A在有丝分裂期间处于闭合状态，特别是在胞质分裂期间。降低Ric-8A表达延迟分裂细胞的分裂时间，这与细胞间桥长度增加和多核化相关。在胞质分裂过程中，Ric-8A与Vps 34共定位在中间体沿着，与Gαi和LGN一起，在那里这些蛋白质起调节Vps 34磷脂酰肌醇3-激酶活性的作用。
Resistance to inhibitors of cholinesterase (Ric)-8A is a guanine nucleotide exchange factor for Gαi, Gαq, and Gα12/13, which is implicated in cell signaling and as a molecular chaperone required for the initial association of nascent Gα subunits with cellular membranes. Ric-8A, Gαi subunits, and their regulators are localized at the midbody prior to abscission and linked to the final stages of cell division. Here, we identify a molecular mechanism by which Ric-8A affects cytokinesis and abscission by controlling Vps34 activity. We showed that Ric-8A protein expression is post-transcriptionally controlled during the cell cycle reaching its maximum levels at mitosis. A FRET biosensor created to measure conformational changes in Ric-8A by FLIM (Fluorescence Lifetime Imaging Microscopy) revealed that Ric-8A was in a close-state during mitosis and particularly so at cytokinesis. Lowering Ric-8A expression delayed the abscission time of dividing cells, which correlated with increased intercellular bridge length and multinucleation. During cytokinesis, Ric-8A co-localized with Vps34 at the midbody along with Gαi and LGN, where these proteins functioned to regulate Vps34 phosphatidylinositol 3-kinase activity.
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影响因子：
19
作者：
Funderburk SF;Wang QJ;Yue Z
通讯作者：
Yue Z
影响因子：
7.3
作者：
Alexander J;Lim D;Joughin BA;Hegemann B;Hutchins JR;Ehrenberger T;Ivins F;Sessa F;Hudecz O;Nigg EA;Fry AM;Musacchio A;Stukenberg PT;Mechtler K;Peters JM;Smerdon SJ;Yaffe MB
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Yaffe MB
影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
影响因子：
7.8
作者：
Cho, Hyeseon;Kehrl, John H.
通讯作者：
Kehrl, John H.
影响因子：
4.6
作者：
Afshar, K;Willard, FS;Gönczy, P
通讯作者：
Gönczy, P