{"title":"Unconventional localization of PAI-1 in PML bodies: A possible link with cellular growth of endothelial cells","authors":"Pragya Gehlot , Daniela Brünnert , Vibha Kaushik , Arpana Yadav , Saloni Bage , Kritika Gaur , Mahesh Saini , Jens Ehrhardt , Gowrang Kasaba Manjunath , Abhishek Kumar , Neena Kasliwal , Ajay Kumar Sharma , Marek Zygmunt , Pankaj Goyal","doi":"10.1016/j.bbrep.2024.101793","DOIUrl":null,"url":null,"abstract":"<div><p>Plasminogen activator inhibitor-1 (PAI-1/Serpin E1) is classically known for its antifibrinolytic activity via inhibiting uPA and tPA of the fibrinolytic pathway. PAI-1 has a paradoxical role in tumor progression, and its molecular functions are poorly understood. PAI-1 is a widely accepted secretory protease inhibitor, however, a study suggested the localization of PAI-1 in the cytoplasm and the nucleus. Besides the plethora of its biological functions as a secretory protein, intracellular localization, and functions of PAI-1 remain unexplored at the molecular level. In this study, using various <em>in silico</em> approaches, we showed that PAI-1 possesses a nuclear export signal. Using the CRM1-specific inhibitor leptomycin B, we demonstrated that PAI-1 has a functional CRM1-dependent NES, indicating the possibility of its nuclear localization. Further, we confirm that PAI-1 is localized in the nucleus of endothelial cells using fluorescence microscopy and immunoprecipitation. Notably, we identified an unconventional distribution of PAI-1 in the PML bodies of the nucleus of normal endothelial cells, while the protein was restricted in the cytoplasm of slow-growing cells. The data showed that the localization of PAI-1 in PML bodies is highly correlated with the growth potential of endothelial cells. This conditional nucleocytoplasmic shuttling of PAI-1 during the aging of cells could impart a strong link to its age-related functions and tumor progression. Together, this study identifies the novel behavior of PAI-1 that might be linked with cell aging and may be able to unveil the elusive role of PAI-1 in tumor progression.</p></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"39 ","pages":"Article 101793"},"PeriodicalIF":2.3000,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2405580824001572/pdfft?md5=b929507b1906f3ae6f9d430293b2109a&pid=1-s2.0-S2405580824001572-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemistry and Biophysics Reports","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2405580824001572","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Plasminogen activator inhibitor-1 (PAI-1/Serpin E1) is classically known for its antifibrinolytic activity via inhibiting uPA and tPA of the fibrinolytic pathway. PAI-1 has a paradoxical role in tumor progression, and its molecular functions are poorly understood. PAI-1 is a widely accepted secretory protease inhibitor, however, a study suggested the localization of PAI-1 in the cytoplasm and the nucleus. Besides the plethora of its biological functions as a secretory protein, intracellular localization, and functions of PAI-1 remain unexplored at the molecular level. In this study, using various in silico approaches, we showed that PAI-1 possesses a nuclear export signal. Using the CRM1-specific inhibitor leptomycin B, we demonstrated that PAI-1 has a functional CRM1-dependent NES, indicating the possibility of its nuclear localization. Further, we confirm that PAI-1 is localized in the nucleus of endothelial cells using fluorescence microscopy and immunoprecipitation. Notably, we identified an unconventional distribution of PAI-1 in the PML bodies of the nucleus of normal endothelial cells, while the protein was restricted in the cytoplasm of slow-growing cells. The data showed that the localization of PAI-1 in PML bodies is highly correlated with the growth potential of endothelial cells. This conditional nucleocytoplasmic shuttling of PAI-1 during the aging of cells could impart a strong link to its age-related functions and tumor progression. Together, this study identifies the novel behavior of PAI-1 that might be linked with cell aging and may be able to unveil the elusive role of PAI-1 in tumor progression.
期刊介绍：
Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.
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