Granulin and granulin repeats interact with the Tat•P-TEFb complex and inhibit Tat transactivation
Granulin and granulin repeats interact with the Tat•P-TEFb complex and inhibit Tat transactivation
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DOI：
10.1074/jbc.m409575200
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发表时间：
2005-04-08
影响因子：
4.8
通讯作者：
Pe'ery, T
中科院分区：
文献类型：
--
作者：
Hoque, M;Tian, B;Pe'ery, T
细胞正转录延伸因子b(P-TEFb)含有细胞周期蛋白T1和细胞周期蛋白依赖性蛋白9(CDK9)，与人类免疫缺陷病毒1型(HIV-1)调节蛋白TAT相互作用，使病毒能够转录和复制。细胞周期蛋白T1是一种异常长的细胞周期蛋白，由细胞调节蛋白参与。以往的研究表明，颗粒蛋白/上皮蛋白前体(GEP)结合细胞周期蛋白T1富含组氨酸的区域，抑制P-TEFb功能。GEP由序列和性质不同的重复序列组成。GEP还直接与TAT结合。在这里，我们证明了GEP及其一些组成的颗粒蛋白重复序列可以通过TAT抑制HIV-1的转录，而不直接与细胞周期蛋白T1结合。颗粒蛋白与TAT和细胞周期蛋白T1的相互作用在结合部位和二价阳离子需求方面有所不同，我们发现颗粒蛋白重复序列与TAT和细胞周期蛋白T1有不同的结合。颗粒蛋白DE和E与TAT结合，但不直接与细胞周期蛋白T1相互作用。这些颗粒存在于与TAT和P-TEFb的复合体中，其中TAT在细胞蛋白质之间形成了一座桥梁。颗粒蛋白DE和E抑制HIV-1LTR的转录和病毒基因组的基因表达，增加了开发基于颗粒的病毒感染抑制剂的可能性。
The cellular positive transcription elongation factor b (P-TEFb), containing cyclin T1 and cyclin-dependent kinase 9 (CDK9), interacts with the human immunodeficiency virus, type 1 (HIV-1) regulatory protein Tat to enable viral transcription and replication. Cyclin T1 is an unusually long cyclin and is engaged by cellular regulatory proteins. Previous studies showed that the granulin/epithelin precursor (GEP) binds the histidine-rich region of cyclin T1 and inhibits P-TEFb function. GEP is composed of repeats that vary in sequence and properties. GEP also binds directly to Tat. Here we show that GEP and some of its constituent granulin repeats can inhibit HIV-1 transcription via Tat without directly binding to cyclin T1. The interactions of granulins with Tat and cyclin T1 differ with respect to their binding sites and divalent cation requirements, and we identified granulin repeats that bind differentially to Tat and cyclin T1. Granulins DE and E bind Tat but do not interact directly with cyclin T1. These granulins are present in complexes with Tat and P-TEFb in which Tat forms a bridge between the cellular proteins. Granulins DE and E repress transcription from the HIV-1 LTR and gene expression from the viral genome, raising the possibility of developing granulin-based inhibitors of viral infection.