Ylösmäki Leena, Schmotz Constanze, Ylösmäki Erkko, Saksela Kalle
Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Virology. 2015 Oct;484:146-152. doi: 10.1016/j.virol.2015.06.009. Epub 2015 Jun 19.
The non-structural protein-1 (NS1) of influenza A virus binds the p85β subunit of phosphoinositide 3-kinase (PI3K) to induce PI3K activity in the infected cells. Some virus strains encode NS1 containing a motif that binds tightly to the SH3 domain of the cellular adapter proteins Crk and CrkL to potentiate NS1-induced PI3K activation. Here we show that this potentiation involves reorganization of the natural CrkL-p85β complex into a novel trimeric complex where NS1 serves as a bridging factor. Of note, NS1 proteins that lack the SH3 binding capacity can also associate with CrkL, but in a less stable trimeric complex mediated by p85β. The data presented here establish Crk proteins as general host cell cofactors of NS1, and show that the enhanced PI3K activation by SH3 binding-competent NS1 variants is mediated by a more efficient tethering of Crk proteins to the NS1-PI3K complex.
甲型流感病毒的非结构蛋白1（NS1）与磷酸肌醇3激酶（PI3K）的p85β亚基结合，以诱导被感染细胞中的PI3K活性。一些病毒株编码的NS1含有一个基序，该基序与细胞衔接蛋白Crk和CrkL的SH3结构域紧密结合，以增强NS1诱导的PI3K激活。在此我们表明，这种增强作用涉及将天然的CrkL-p85β复合物重组成一种新型三聚体复合物，其中NS1作为一个桥梁因子。值得注意的是，缺乏SH3结合能力的NS1蛋白也能与CrkL结合，但存在于由p85β介导的稳定性较低的三聚体复合物中。本文提供的数据确立了Crk蛋白作为NS1的一般宿主细胞辅助因子的地位，并表明具有SH3结合能力的NS1变体增强的PI3K激活是由Crk蛋白更有效地拴系到NS1-PI3K复合物介导的。
