Epstein-Barr virus immediate-early protein BRLF1 induces the lytic form of viral replication through a mechanism involving phosphatidylinositol-3 kinase activation
Epstein-Barr virus immediate-early protein BRLF1 induces the lytic form of viral replication through a mechanism involving phosphatidylinositol-3 kinase activation
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DOI：
10.1128/jvi.75.13.6135-6142.2001
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发表时间：
2001-07-01
影响因子：
5.4
通讯作者：
Kenney, S
中科院分区：
文献类型：
--
作者：
Darr, CD;Mauser, A;Kenney, S
EB病毒（EBV）即早期（IE）蛋白BRLF 1的表达在大多数EBV阳性细胞系中诱导裂解形式的病毒复制。BRLF 1是一种转录激活因子，可直接与某些EBV裂解基因启动子中富含GC的基序结合。然而，BRLF 1激活转录的其他IE蛋白，BZLF 1，通过一个间接的机制，我们以前表明，需要激活的应激丝裂原活化蛋白激酶。在这里，我们证明BRLF 1激活宿主细胞中的磷脂酰肌醇-3（PI 3）激酶信号。我们发现，特异性PI 3激酶抑制剂LY 294002完全消除了BRLF 1腺病毒载体诱导EBV感染的裂解形式的能力，而不影响BZLF 1腺病毒载体诱导的裂解感染。此外，我们证明了BRLF 1诱导的转录激活中PI 3激酶激活的要求是启动子依赖性的。SM早期启动子的BRLF 1激活（通过直接结合机制发生）不需要PI 3激酶激活，而IE BZLF 1和早期BMRF 1启动子的激活需要PI 3激酶激活。因此，BRLF 1诱导转录激活的机制显然有两种。
Expression of the Epstein-Barr virus (EBV) immediate-early (IE) protein BRLF1 induces the lytic form of viral replication in most EBV-positive cell lines. BRLF1 is a transcriptional activator that binds directly to a GC-rich motif present in some EBV lytic gene promoters. However, BRLF1 activates transcription of the other IE protein, BZLF1, through an indirect mechanism which we previously showed to require activation of the stress mitogen-activated protein kinases. Here we demonstrate that BRLF1 activates phosphatidylinositol-3 (PI3) kinase signaling in host cells. We show that the specific PI3 kinase inhibitor, LY294002, completely abrogates the ability of a BRLF1 adenovirus vector to induce the lytic form of EBV infection, while not affecting lytic infection induced by a BZLF1 adenovirus vector. Furthermore, we demonstrate that the requirement for PI3 kinase activation in BRLF1-induced transcriptional activation is promoter dependent. BRLF1 activation of the SM early promoter (which occurs through a direct binding mechanism) does not require PI3 kinase activation, whereas activation of the IE BZLF1 and early BMRF1 promoters requires PI3 kinase activation. Thus, there are clearly two separate mechanisms by which BRLF1 induces transcriptional activation.