Functional analysis of human T lymphotropic virus type 2 Tax proteins
Functional analysis of human T lymphotropic virus type 2 Tax proteins
复制标题
人类嗜T淋巴细胞病毒2型Tax蛋白的功能分析
作者：
N. Sheehy;L. Lillis;K. Watters;Martha J. Lewis;V. Gautier;W. Hall
人类嗜T淋巴细胞病毒1型(HTLV-1)和2型(HTLV-2)编码的TAX蛋白既是病毒长末端重复序列(LTR)的转录激活子，又是通过CREB和NFkB途径的细胞启动子。与HTLV-1不同，HTLV-2被划分为A、B、C和D四个不同的遗传亚型，通过对它们的核苷酸序列和Tax蛋白的大小和氨基酸序列的系统发育分析来定义它们。结果除TAX 2AMo蛋白外，其余两种蛋白在Jurkat和293T细胞中均不能反式激活病毒LTR或NFkB启动子。活性的丧失与表达水平或亚细胞分布的改变无关，因为所有TAX-2蛋白主要位于转基因细胞的细胞质中。对两个失活的Tax 2A蛋白相对于Mo的序列分析表明，其中一个在蛋白质的中心区域有六个氨基酸变化，另一个在蛋白质的中心区有一个变化。发生在Mo的氨基和极端羧基末端的突变会导致LTR的丧失，但不会导致NFkB的激活，而发生在蛋白质中心区的突变似乎会取消这两个启动子的反式激活。对Tax-1、Tax-2AMo和Tax-2B的反式激活表型的分析表明，在所有三种Tax蛋白中，激活LTR和NFkB所需的结构域非常相似，但并不完全相同。结论我们的结果表明，来自不同分离株的两个Tax-2A蛋白的活性丧失与CREB或CREB和NFkB途径激活所需的结构域中相对于Mo的多个氨基酸变化有关，这些结构域在Tax 2B和Tax 1中非常相似但不相同。在2A病毒中，Tax功能的丧失可能对它们的生物学和致病特性产生影响。
BackgroundThe Tax proteins encoded by human T lymphotropic virus type 1 (HTLV-1) and type 2 (HTLV-2) are transcriptional activators of both the viral long terminal repeat (LTR) and cellular promoters via the CREB and NFkB pathways. In contrast to HTLV-1, HTLV-2 has been classified into four distinct genetic subtypes A, B, C and D defined by phylogenetic analysis of their nucleotide sequences and the size and amino acid sequence of their Tax proteins. In the present study we have analysed and compared the transactivating activities of three Tax 2A and one Tax 2B proteins using LTR and NFkB reporter assays.ResultsWe found that with the exception of the prototype Tax 2A Mo protein, the other two Tax 2A proteins failed to transactivate either the viral LTR or NFkB promoter in Jurkat and 293T cells. Loss of activity was not associated with either expression levels or an alteration in subcellular distribution as all Tax 2 proteins were predominantly located in the cytoplasm of transfected cells. Analysis of the sequence of the two inactive Tax 2A proteins relative to Mo indicated that one had six amino acid changes and the other had one change in the central region of the protein. Mutations present at the amino and the extreme carboxy termini of Mo resulted in the loss of LTR but not NFkB activation whereas those occurring in the central region of the protein appeared to abolish transactivation of both promoters. Analysis of the transactivation phenotypes of Tax 1, Tax 2A Mo and Tax 2B containing mutations identified in the present study or previously characterised Tax mutations showed that domains required for LTR and NFkB activation are very similar but not identical in all three Tax proteins.ConclusionOur results suggest that loss of activity of two Tax 2A proteins derived from different isolates is associated with multiple amino acid changes relative to Mo in domains required for the activation of the CREB or CREB and NFkB pathways and that these domains are very similar but not identical in Tax 2B and Tax 1. The loss of Tax function in 2A viruses may have implications for their biological and pathogenic properties.
影响因子：
2.2
作者：
Diana F. Roucoux;E. Murphy
通讯作者：
Diana F. Roucoux;E. Murphy