Influenza A virus NS1 protein targets poly(A)-binding protein II of the cellular 3′-end processing machinery
Influenza A virus NS1 protein targets poly(A)-binding protein II of the cellular 3′-end processing machinery
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DOI：
10.1093/emboj/18.8.2273
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发表时间：
1999-04-15
期刊：
影响因子：
11.4
通讯作者：
Krug, RM
中科院分区：
文献类型：
--
作者：
Chen, ZY;Li, YZ;Krug, RM
甲型流感病毒NS 1蛋白（NS 1A蛋白）通过其效应结构域靶向细胞3 '端加工机构的多聚腺苷酸结合蛋白II（PABII）。在体外，NS 1A蛋白结合PABII蛋白，并在体内导致PABII蛋白分子从核斑点重新定位为均匀分布在整个核质中。在体外，NS 1A蛋白抑制PABII刺激由聚（A）聚合酶（PAP）催化的长聚（A）尾的进行性合成的能力。这种抑制也在体内发生在流感病毒感染的细胞中，其中NS 1A蛋白通过其效应结构域引起含有短（类似于12个核苷酸）聚（A）尾的细胞前mRNA的核积累。因此，尽管NS 1A蛋白也结合切割和多聚腺苷酸化特异性因子（CPSF）的30 kDa亚基，但在病毒感染的细胞中仍然发生一些细胞前mRNA的3'切割，随后是PAP催化的短聚（A）尾的添加。由于NS 1A蛋白抑制PABII功能，这些短poly（A）尾的后续延伸被阻断。PABII的核-胞质穿梭（一种在细胞mRNA的核输出中涉及该蛋白的活性）也被NS 1A蛋白抑制。体外试验表明，30 kDa CPSF和PABII蛋白结合到NS 1A蛋白效应结构域的非重叠区域，并表明这两种3'加工蛋白也直接相互结合。
Influenza A virus NS1 protein (NS1A protein) via its effector domain targets the poly(A)-binding protein II (PABII) of the cellular 3'-end processing machinery. In vitro the NS1A protein binds the PABII protein, and in vivo causes PABII protein molecules to relocalize from nuclear speckles to a uniform distribution throughout the nucleoplasm. In vitro the NS1A protein inhibits the ability of PABII to stimulate the processive synthesis of long poly(A) tails catalyzed by poly(A) polymerase (PAP), Such inhibition also occurs in vivo in influenza virus-infected cells, where the NS1A protein via its effector domain causes the nuclear accumulation of cellular pre-mRNAs which contain short (similar to 12 nucleotide) poly(A) tails. Consequently, although the NS1A protein also binds the 30 kDa subunit of the cleavage and polyadenylation specificity factor (CPSF), 3' cleavage of some cellular pre-mRNAs still occurs in virus-infected cells, followed by the PAP-catalyzed addition of short poly(A) tails. Subsequent elongation of these short poly(A) tails is blocked because the NS1A protein inhibits PABII function. Nuclear-cytoplasmic shuttling of PABII, an activity implicating this protein in the nuclear export of cellular mRNAs, is also inhibited by the NS1A protein, lit vitro assays suggest that the 30 kDa CPSF and PABII proteins bind to non-overlapping regions of the NS1A protein effector domain and indicate that these two 3' processing proteins also directly bind to each other.