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PI(3,4,5)P3 变构调节转录激活蛋白 1 控制锥虫抗原变异。

PI(3,4,5)P3 allosteric regulation of repressor activator protein 1 controls antigenic variation in trypanosomes.

机构信息

Institute of Parasitology, McGill University, Sainte-Anne-de-Bellevue, Montreal, Canada.

Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Canada.

出版信息

Elife. 2023 Nov 29;12:RP89331. doi: 10.7554/eLife.89331.

DOI:10.7554/eLife.89331
PMID:38019264
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10686619/
Abstract

African trypanosomes evade host immune clearance by antigenic variation, causing persistent infections in humans and animals. These parasites express a homogeneous surface coat of variant surface glycoproteins (VSGs). They transcribe one out of hundreds of VSG genes at a time from telomeric expression sites (ESs) and periodically change the VSG expressed by transcriptional switching or recombination. The mechanisms underlying the control of VSG switching and its developmental silencing remain elusive. We report that telomeric ES activation and silencing entail an on/off genetic switch controlled by a nuclear phosphoinositide signaling system. This system includes a nuclear phosphatidylinositol 5-phosphatase (PIP5Pase), its substrate PI(3,4,5)P3, and the repressor-activator protein 1 (RAP1). RAP1 binds to ES sequences flanking VSG genes via its DNA binding domains and represses VSG transcription. In contrast, PI(3,4,5)P3 binds to the N-terminus of RAP1 and controls its DNA binding activity. Transient inactivation of PIP5Pase results in the accumulation of nuclear PI(3,4,5)P3, which binds RAP1 and displaces it from ESs, activating transcription of silent ESs and VSG switching. The system is also required for the developmental silencing of VSG genes. The data provides a mechanism controlling reversible telomere silencing essential for the periodic switching in VSG expression and its developmental regulation.

摘要

非洲锥虫通过抗原变异逃避宿主免疫清除，导致人类和动物的持续感染。这些寄生虫表达同质的表面糖蛋白（VSG）覆盖层。它们从端粒表达位点（ES）转录数百个 VSG 基因中的一个，并且通过转录开关或重组周期性改变表达的 VSG。控制 VSG 开关及其发育沉默的机制仍然难以捉摸。我们报告说，端粒 ES 的激活和沉默需要由核磷酸肌醇信号系统控制的开/关遗传开关。该系统包括核磷脂酰肌醇 5-磷酸酶（PIP5Pase）、其底物 PI（3,4,5）P3 和阻遏物-激活物蛋白 1（RAP1）。RAP1 通过其 DNA 结合结构域与 VSG 基因侧翼的 ES 序列结合，从而抑制 VSG 转录。相比之下，PI（3,4,5）P3 与 RAP1 的 N 端结合，并控制其 DNA 结合活性。PIP5Pase 的瞬时失活导致核 PI（3,4,5）P3 的积累，其与 RAP1 结合并将其从 ES 中置换出来，从而激活沉默 ES 的转录和 VSG 开关。该系统还需要用于 VSG 基因的发育沉默。该数据提供了一种控制可逆端粒沉默的机制，对于 VSG 表达的周期性开关及其发育调节至关重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/05ec69143ea4/elife-89331-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/788e72a3242e/elife-89331-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/16a1a2590385/elife-89331-fig1-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/1501629d4b4f/elife-89331-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/fe2ec4595150/elife-89331-fig2-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/efd912c7ae9b/elife-89331-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/62644e1a0ba9/elife-89331-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/c89c0585c41e/elife-89331-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/d7512fb5403c/elife-89331-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/951864809fac/elife-89331-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/05ec69143ea4/elife-89331-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/788e72a3242e/elife-89331-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/16a1a2590385/elife-89331-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/61676fe162f3/elife-89331-fig1-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/585ebe9b5fce/elife-89331-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/9e195e6851f7/elife-89331-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/1501629d4b4f/elife-89331-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/fe2ec4595150/elife-89331-fig2-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/efd912c7ae9b/elife-89331-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/62644e1a0ba9/elife-89331-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/c89c0585c41e/elife-89331-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/d7512fb5403c/elife-89331-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/951864809fac/elife-89331-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ddd/10686619/05ec69143ea4/elife-89331-fig5-figsupp1.jpg

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