Cooperation between viral interferon regulatory factor 4 and RTA to activate a subset of Kaposi's sarcoma-associated herpesvirus lytic promoters.
Cooperation between viral interferon regulatory factor 4 and RTA to activate a subset of Kaposi's sarcoma-associated herpesvirus lytic promoters.
复制标题
病毒干扰素调节因子 4 和 RTA 合作激活卡波西肉瘤相关疱疹病毒裂解启动子的子集。
DOI：
10.1128/jvi.00694-11
复制
发表时间：
2012
影响因子：
5.4
通讯作者：
Wilson,AngusC
中科院分区：
文献类型：
--
作者：
Xi,Xiangmei;Persson,LindaM;O'Brien,MichaelW;Mohr,Ian;Wilson,AngusC
四种卡波西肉瘤相关疱疹病毒（KSHV）编码的干扰素（IFN）调节因子同源物（vIRF 1至vIRF 4）用于对抗先天免疫防御和抑制p53。vIRF基因串联排列，但功能和表达不同。在KSHV感染的渗出性淋巴瘤细胞系中，K10.5/vIRF 3和K11/vIRF 2 mRNA在潜伏期很容易检测到，而K9/vIRF 1和K10/vIRF 4 mRNA在再激活期间上调。在这里，我们表明，K10/vIRF 4启动子响应KSHV感染的细胞中的裂解开关蛋白RTA，但在未感染的细胞基本上是无反应的。RTA与vIRF 4的共表达足以恢复调节，这是其他vIRFs不共享的特性。K9/vIRF 1启动子的行为类似，并且感染性病毒的产生通过vIRF 4的存在而增强。协同作用需要vIRF 4的DNA结合结构域（DBD）和C-末端IRF同源区。在vIRF 4的推定的DNA识别螺旋内的精氨酸残基或相邻CxxC基序的不变半胱氨酸的突变废除与RTA的合作，在后一种情况下，通过防止自缔合。RTA的寡聚化和反式激活功能对于协同作用也是必不可少的。K10/vIRF 4启动子包含两个转录起始位点（TSS），并且包含近端启动子的105-bp片段对vIRF 4/RTA响应。当两种病毒蛋白都存在时，细胞因子与该片段的结合发生改变，这表明了转录协同作用的可能机制。依赖于由宿主或病毒基因组编码的辅调节子提供了一种扩展主调节子（如RTA）的调节潜力的优雅策略。
The four Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded interferon (IFN) regulatory factor homologues (vIRF1 to vIRF4) are used to counter innate immune defenses and suppress p53. The vIRF genes are arranged in tandem but differ in function and expression. In KSHV-infected effusion lymphoma lines, K10.5/vIRF3 and K11/vIRF2 mRNAs are readily detected during latency, whereas K9/vIRF1 and K10/vIRF4 mRNAs are upregulated during reactivation. Here we show that the K10/vIRF4 promoter responds to the lytic switch protein RTA in KSHV-infected cells but is essentially unresponsive in uninfected cells. Coexpression of RTA with vIRF4 is sufficient to restore regulation, a property not shared by other vIRFs. The K9/vIRF1 promoter behaves similarly, and production of infectious virus is enhanced by the presence of vIRF4. Synergy requires the DNA-binding domain (DBD) and C-terminal IRF homology regions of vIRF4. Mutations of arginine residues within the putative DNA recognition helix of vIRF4 or the invariant cysteines of the adjacent CxxC motif abolish cooperation with RTA, in the latter case by preventing self-association. The oligomerization and transactivation functions of RTA are also essential for synergy. The K10/vIRF4 promoter contains two transcription start sites (TSSs), and a 105-bp fragment containing the proximal promoter is responsive to vIRF4/RTA. Binding of a cellular factor(s) to this fragment is altered when both viral proteins are present, suggesting a possible mechanism for transcriptional synergy. Reliance on coregulators encoded by either the host or viral genome provides an elegant strategy for expanding the regulatory potential of a master regulator, such as RTA.