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腺病毒蛋白 E4orf4 与极性蛋白 Par3 相互作用，诱导核破裂和肿瘤细胞死亡。

Adenoviral protein E4orf4 interacts with the polarity protein Par3 to induce nuclear rupture and tumor cell death.

机构信息

Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.

Oncology, Centre de Recherche du CHU de Québec-Université Laval, Québec City, Québec, Canada.

出版信息

J Cell Biol. 2020 Apr 6;219(4). doi: 10.1083/jcb.201805122.

DOI:10.1083/jcb.201805122
PMID:32328642
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7147092/
Abstract

The tumor cell-selective killing activity of the adenovirus type 2 early region 4 ORF4 (E4orf4) protein is poorly defined at the molecular level. Here, we show that the tumoricidal effect of E4orf4 is typified by changes in nuclear dynamics that depend on its interaction with the polarity protein Par3 and actomyosin contractility. Mechanistically, E4orf4 induced a high incidence of nuclear bleb formation and repetitive nuclear ruptures, which promoted nuclear efflux of E4orf4 and loss of nuclear integrity. This process was regulated by nucleocytoskeletal connections, Par3 clustering proximal to nuclear lamina folds, and retrograde movement of actin bundles that correlated with nuclear ruptures. Significantly, Par3 also regulated the incidence of spontaneous nuclear ruptures facilitated by the downmodulation of lamins. This work uncovered a novel role for Par3 in controlling the actin-dependent forces acting on the nuclear envelope to remodel nuclear shape, which might be a defining feature of tumor cells that is harnessed by E4orf4.

摘要

腺病毒 2 型早期区域 4 ORF4（E4orf4）蛋白的肿瘤细胞选择性杀伤活性在分子水平上尚未明确。在这里，我们表明 E4orf4 的杀瘤作用以核动力学变化为特征，这依赖于其与极性蛋白 Par3 的相互作用以及肌动球蛋白的收缩性。在机制上，E4orf4 诱导了大量核泡形成和核反复破裂，从而促进了 E4orf4 的核外流和核完整性的丧失。这个过程受到核质连接、靠近核层折叠的 Par3 聚集以及与核破裂相关的肌动蛋白束逆行运动的调节。重要的是，Par3 还调节了由于层粘连蛋白下调而促进的自发核破裂的发生率。这项工作揭示了 Par3 在控制作用于核膜的肌动蛋白依赖性力以重塑核形状方面的新作用，这可能是 E4orf4 利用的肿瘤细胞的一个特征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/b608c6e00f22/JCB_201805122_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/fd5e77dcf662/JCB_201805122_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/17c1d3bee775/JCB_201805122_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/5cd62c08de6a/JCB_201805122_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/69a8c784d647/JCB_201805122_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/adc485ea9eb1/JCB_201805122_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/e28d27b2a5a1/JCB_201805122_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/bdcfcb096225/JCB_201805122_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/11cc66de0440/JCB_201805122_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/7bbbadf1d0ea/JCB_201805122_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/a3da53b66b11/JCB_201805122_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/6c7bb57b6593/JCB_201805122_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/7147b4bf4263/JCB_201805122_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/483b5a1561a9/JCB_201805122_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/ca5bdd6b5c1f/JCB_201805122_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/b608c6e00f22/JCB_201805122_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/fd5e77dcf662/JCB_201805122_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/17c1d3bee775/JCB_201805122_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/5cd62c08de6a/JCB_201805122_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/69a8c784d647/JCB_201805122_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/adc485ea9eb1/JCB_201805122_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/e28d27b2a5a1/JCB_201805122_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/bdcfcb096225/JCB_201805122_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/11cc66de0440/JCB_201805122_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/7bbbadf1d0ea/JCB_201805122_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/a3da53b66b11/JCB_201805122_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/6c7bb57b6593/JCB_201805122_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/7147b4bf4263/JCB_201805122_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/483b5a1561a9/JCB_201805122_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/ca5bdd6b5c1f/JCB_201805122_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/449d/7147092/b608c6e00f22/JCB_201805122_Fig10.jpg

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The Biology of the Nuclear Envelope and Its Implications in Cancer Biology.核膜的生物学及其在癌症生物学中的意义。
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