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FAK 通过独立于激酶活性的方式调节张力向核内的传递和血管内皮细胞转录组。

FAK regulates tension transmission to the nucleus and endothelial transcriptome independent of kinase activity.

机构信息

Department of Pharmacology & Regenerative Medicine and Center for Lung and Vascular Biology, Chicago, IL, USA.

Department of Biomedical Engineering, Chicago, IL, USA.

出版信息

Cell Rep. 2024 Jun 25;43(6):114297. doi: 10.1016/j.celrep.2024.114297. Epub 2024 Jun 1.

DOI:10.1016/j.celrep.2024.114297
PMID:38824643
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11262709/
Abstract

The mechanical environment generated through the adhesive interaction of endothelial cells (ECs) with the matrix controls nuclear tension, preventing aberrant gene synthesis and the transition from restrictive to leaky endothelium, a hallmark of acute lung injury (ALI). However, the mechanisms controlling tension transmission to the nucleus and EC-restrictive fate remain elusive. Here, we demonstrate that, in a kinase-independent manner, focal adhesion kinase (FAK) safeguards tension transmission to the nucleus to maintain EC-restrictive fate. In FAK-depleted ECs, robust activation of the RhoA-Rho-kinase pathway increased EC tension and phosphorylation of the nuclear envelope protein, emerin, activating DNMT3a. Activated DNMT3a methylates the KLF2 promoter, impairing the synthesis of KLF2 and its target S1PR1 to induce the leaky EC transcriptome. Repleting FAK (wild type or kinase dead) or inhibiting RhoA-emerin-DNMT3a activities in damaged lung ECs restored KLF2 transcription of the restrictive EC transcriptome. Thus, FAK sensing and control of tension transmission to the nucleus govern restrictive endothelium to maintain lung homeostasis.

摘要

内皮细胞 (ECs) 与基质的黏附相互作用产生的机械环境控制核张力，防止异常基因合成和从限制型向渗漏型内皮的转变，这是急性肺损伤 (ALI) 的标志。然而，控制张力向核传递和 EC 限制命运的机制仍不清楚。在这里，我们证明，在激酶非依赖性方式中，粘着斑激酶 (FAK) 保护核张力的传递以维持 EC 限制命运。在 FAK 耗尽的 EC 中，RhoA-Rho 激酶途径的强烈激活增加了 EC 张力和核包膜蛋白 emerin 的磷酸化，激活 DNMT3a。激活的 DNMT3a 甲基化 KLF2 启动子，损害 KLF2 的合成及其靶标 S1PR1，以诱导渗漏型 EC 转录组。在受损的肺 EC 中补充 FAK（野生型或激酶失活）或抑制 RhoA-emerin-DNMT3a 活性，可恢复限制性 EC 转录组的 KLF2 转录。因此，FAK 对核张力传递的感知和控制决定了限制型内皮，以维持肺内稳态。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/eefb003c496a/nihms-2005235-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/111a60939174/nihms-2005235-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/79b889f589e6/nihms-2005235-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/ad058d444115/nihms-2005235-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/0cc085f20785/nihms-2005235-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/f61de4b613c5/nihms-2005235-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/27724dd044c2/nihms-2005235-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/eefb003c496a/nihms-2005235-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/111a60939174/nihms-2005235-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/79b889f589e6/nihms-2005235-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/ad058d444115/nihms-2005235-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/0cc085f20785/nihms-2005235-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/f61de4b613c5/nihms-2005235-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/27724dd044c2/nihms-2005235-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/180f/11262709/eefb003c496a/nihms-2005235-f0008.jpg

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