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临近标记揭示了微管接头对后期促进复合物/周期蛋白体的空间调节作用。

Proximity Labeling Reveals Spatial Regulation of the Anaphase-Promoting Complex/Cyclosome by a Microtubule Adaptor.

机构信息

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14850, United States.

Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14850, United States.

出版信息

ACS Chem Biol. 2022 Sep 16;17(9):2605-2618. doi: 10.1021/acschembio.2c00527. Epub 2022 Aug 11.

DOI:10.1021/acschembio.2c00527
PMID:35952650
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9933862/
Abstract

The anaphase-promoting complex/cyclosome (APC/C) coordinates advancement through mitosis via temporally controlled polyubiquitination events. Despite the long-appreciated spatial organization of key events in mitosis mediated largely by cytoskeletal networks, the spatial regulation of APC/C, the major mitotic E3 ligase, is poorly understood. We describe a microtubule-resident protein, PLEKHA5, as an interactor of APC/C and spatial regulator of its activity in mitosis. Microtubule-localized proximity biotinylation tools revealed that PLEKHA5 depletion decreased APC/C association with the microtubule cytoskeleton, which prevented efficient loading of APC/C with its coactivator CDC20 and led to reduced APC/C E3 ligase activity. PLEKHA5 knockdown delayed mitotic progression, causing accumulation of APC/C substrates dependent upon the PLEKHA5-APC/C interaction in microtubules. We propose that PLEKHA5 functions as an adaptor of APC/C that promotes its subcellular localization to microtubules and facilitates its activation by CDC20, thus ensuring the timely turnover of key mitotic APC/C substrates and proper progression through mitosis.

摘要

后期促进复合物/周期蛋白体（APC/C）通过时间控制的多泛素化事件协调有丝分裂的进展。尽管有丝分裂中关键事件的空间组织长期以来主要由细胞骨架网络介导，但 APC/C 的空间调控，即主要的有丝分裂 E3 连接酶，仍知之甚少。我们描述了一种微管驻留蛋白 PLEKHA5，它是 APC/C 的相互作用蛋白和其在有丝分裂中活性的空间调节剂。微管定位的邻近生物素化工具表明，PLEKHA5 耗竭会降低 APC/C 与微管细胞骨架的结合，从而阻止 APC/C 与其共激活因子 CDC20 的有效加载，并导致 APC/C E3 连接酶活性降低。PLEKHA5 敲低会延迟有丝分裂进程，导致 APC/C 底物的积累，这些底物依赖于 PLEKHA5-APC/C 在微管中的相互作用。我们提出 PLEKHA5 作为 APC/C 的衔接物发挥作用，促进其亚细胞定位到微管，并促进其与 CDC20 的激活，从而确保关键的有丝分裂 APC/C 底物的及时周转和有丝分裂的正常进行。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acf9/9933862/13bc61b85c2a/nihms-1872210-f0009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acf9/9933862/58be830252de/nihms-1872210-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acf9/9933862/51ede3e16ba5/nihms-1872210-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acf9/9933862/6042b0bc5534/nihms-1872210-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acf9/9933862/49891981691c/nihms-1872210-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/acf9/9933862/13bc61b85c2a/nihms-1872210-f0009.jpg

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