文章基本信息

标题：TOE1 is an inhibitor of HIV-1 replication with cell-penetrating capability
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作者：Sabina Sperandio ; Corinne Barat ; Miguel A. Cabrita 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：26
页码：E3392-E3401
DOI：10.1073/pnas.1500857112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceUnderstanding the host response to HIV-1 infection may provide important clues to design new strategies to prevent further infection and viral spread. In this report, we show that the cellular protein Target Of Egr1 (TOE1) can specifically bind to a HIV-1 regulatory sequence, called the transactivator response element, and inhibit its activity. This inhibition is shown to be sufficient to impair viral transcription and replication in HIV-1-infected T cells. We show that TOE1 is secreted from activated primary T cells, mimicking antigen presentation. Secreted forms of TOE1 cross the plasma membrane of neighboring cells and retain HIV-1 inhibitory activity. These results provide new information on a cellular mediator of HIV-1 inhibition and may guide further therapeutic anti-HIV-1 approaches. Target of Egr1 (TOE1) is a nuclear protein localized primarily in nucleoli and Cajal bodies that was identified as a downstream target of the immediate early gene Egr1. TOE1 displays a functional deadenylation domain and has been shown to participate in spliceosome assembly. We report here that TOE1 can function as an inhibitor of HIV-1 replication and show evidence that supports a direct interaction of TOE1 with the viral specific transactivator response element as part of the inhibitory mechanism. In addition, we show that TOE1 can be secreted by activated CD8+ T lymphocytes and can be cleaved by the serine protease granzyme B, one of the main components of cytotoxic granules. Both full-length and cleaved TOE1 can spontaneously cross the plasma membrane and penetrate cells in culture, retaining HIV-1 inhibitory activity. Antiviral potency of TOE1 and its cell-penetrating capability have been identified to lie within a 35-amino-acid region containing the nuclear localization sequence.
关键词：TOE1 ; HIV-1 ; replication ; cell penetrating peptide ; granzyme B