Tripathi Vasvi, Chatterjee Kiran Sankar, Das Ranabir
National Centre for Biological Sciences, Tata Institute of Fundamental Research (TIFR), Bengaluru, India.
Front Cell Dev Biol. 2021 May 13;9:662522. doi: 10.3389/fcell.2021.662522. eCollection 2021.
Viruses interact with the host cellular pathways to optimize cellular conditions for replication. The Human Cytomegalovirus (HCMV) Immediate-Early protein 1 (IE1) is the first viral protein to express during infection. It is a multifunctional and conditionally essential protein for HCMV infection. SUMO signaling regulates several cellular pathways that are also targets of IE1. Consequently, IE1 exploits SUMO signaling to regulate these pathways. The covalent interaction of IE1 and SUMO (IE1-SUMOylation) is well studied. However, the non-covalent interactions between SUMO and IE1 are unknown. We report two SUMO-Interacting Motifs (SIMs) in IE1, one at the end of the core domain and another in the C-terminal domain. NMR titrations showed that IE1-SIMs bind to SUMO1 but not SUMO2. Two critical functions of IE1 are inhibition of SUMOylation of Promyelocytic leukemia protein (PML) and transactivation of viral promoters. Although the non-covalent interaction of IE1 and SUMO is not involved in the inhibition of PML SUMOylation, it contributes to the transactivation activity. The transactivation activity of IE1 was previously correlated to its ability to inhibit PML SUMOylation. Our results suggest that transactivation and inhibition of PML SUMOylation are independent activities of IE1.
病毒与宿主细胞通路相互作用，以优化细胞条件进行复制。人巨细胞病毒（HCMV）立即早期蛋白1（IE1）是感染期间第一个表达的病毒蛋白。它是一种多功能且对HCMV感染有条件必需的蛋白。SUMO信号调节多种细胞通路，这些通路也是IE1的作用靶点。因此，IE1利用SUMO信号来调节这些通路。IE1与SUMO的共价相互作用（IE1- SUMO化）已得到充分研究。然而，SUMO与IE1之间的非共价相互作用尚不清楚。我们报告了IE1中的两个SUMO相互作用基序（SIMs），一个在核心结构域末端，另一个在C末端结构域。核磁共振滴定表明，IE1-SIMs与SUMO1结合，但不与SUMO2结合。IE1的两个关键功能是抑制早幼粒细胞白血病蛋白（PML）的SUMO化和病毒启动子的反式激活。尽管IE1与SUMO的非共价相互作用不参与抑制PML SUMO化，但它有助于反式激活活性。IE1的反式激活活性先前与其抑制PML SUMO化的能力相关。我们的结果表明，反式激活和抑制PML SUMO化是IE1的独立活性。
