Nuclear Phosphatidylinositol 5-Phosphatase Is Essential for Allelic Exclusion of Variant Surface Glycoprotein Genes in Trypanosomes
Nuclear Phosphatidylinositol 5-Phosphatase Is Essential for Allelic Exclusion of Variant Surface Glycoprotein Genes in Trypanosomes
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DOI：
10.1128/mcb.00395-18
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发表时间：
2019-02-01
影响因子：
5.3
通讯作者：
Stuart, Kenneth
中科院分区：
文献类型：
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作者：
Cestari, Igor;McLeland-Wieser, Hilary;Stuart, Kenneth
变异的表面糖蛋白(VSG)基因的等位基因排斥是非洲锥虫通过抗原变异逃避宿主抗体反应的关键。这种寄生虫一次只表达一个类似于2000个VSG基因的机制尚不清楚。我们发现，核磷脂酰肌醇5-磷酸酶(PIP5Pase)与抑制因子激活蛋白1(RAP1)在多蛋白复合体中相互作用，并在控制VSG等位基因排斥中发挥作用。Rap1结合PIP5Pase底物磷脂酰肌醇3，4，5-三磷酸[PI(3，4，5)P3]，PIP5Pase的催化突变抑制PI(3，4，5)P3去磷酸化，导致所有端粒表达位点(Ess)和沉默的亚端粒VSG阵列的VSG同时转录。PIP5Pase和RAP1与端粒Ess结合，特别是在70bp的重复序列和端粒上，它们的结合被PIP5Pase失活或敲除改变，这意味着ES染色质结构的改变。我们的数据提出了一个模型，通过PIP5Pase控制PI(3，4，5)P3与RAP1的结合，从而使端粒和亚端粒VSG基因的RAP1沉默。因此，VSG基因的等位基因排除可能需要控制核磷脂酰肌醇。
Allelic exclusion of variant surface glycoprotein (VSG) genes is essential for African trypanosomes to evade the host antibody response by antigenic variation. The mechanisms by which this parasite expresses only one of its similar to 2,000 VSG genes at a time are unknown. We show that nuclear phosphatidylinositol 5-phosphatase (PIP5Pase) interacts with repressor activator protein 1 (RAP1) in a multiprotein complex and functions in the control of VSG allelic exclusion. RAP1 binds PIP5Pase substrate phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], and catalytic mutation of PIP5Pase that inhibits PI(3,4,5) P3 dephosphorylation results in simultaneous transcription of VSGs from all telomeric expression sites (ESs) and from silent subtelomeric VSG arrays. PIP5Pase and RAP1 bind to telomeric ESs, especially at 70-bp repeats and telomeres, and their binding is altered by PIP5Pase inactivation or knockdown, implying changes in ES chromatin organization. Our data suggest a model whereby PIP5Pase controls PI(3,4,5) P3 binding by RAP1 and, thus, RAP1 silencing of telomeric and subtelomeric VSG genes. Hence, allelic exclusion of VSG genes may entail control of nuclear phosphoinositides.