卡波濟(jì)肉瘤是AIDS患者中最常見(jiàn)的惡性腫瘤,。由于其病原體卡波濟(jì)肉瘤相關(guān)皰疹病毒（KSHV）能在宿主細(xì)胞內(nèi)建立有效的潛伏感染而無(wú)法從體內(nèi)清除,。在普通人群中，KSHV的感染率約為5%,。KSHV維持潛伏感染的機(jī)制是該研究領(lǐng)域的熱點(diǎn)問(wèn)題,。
2009年11月，國(guó)際權(quán)威病毒學(xué)雜志Journal of virology在線發(fā)表了上海巴斯德研究所藍(lán)柯研究組關(guān)于KSHV潛伏感染機(jī)制研究的最新成果,。研究人員通過(guò)酵母雙雜交方法發(fā)現(xiàn)細(xì)胞協(xié)同抑制因子TLE2與KSHV周期調(diào)控開(kāi)關(guān)分子RTA間的相互作用,。TLE2能夠?qū)?xì)胞內(nèi)RTA水平改變做出應(yīng)答，通過(guò)結(jié)合RTA以抑制RTA的轉(zhuǎn)錄激活作用,，有效控制KSHV裂解期基因表達(dá)水平和病毒粒子的釋放,。進(jìn)一步研究發(fā)現(xiàn)，TLE2能夠置換與RTA結(jié)合的轉(zhuǎn)錄激活子,，募集轉(zhuǎn)錄抑制復(fù)合體,，從而實(shí)現(xiàn)對(duì)RTA轉(zhuǎn)錄激活作用的抑制。
該研究首次報(bào)道了TLE2這種新的RTA 結(jié)合蛋白,，并揭示宿主細(xì)胞在KSHV潛伏感染維持中發(fā)揮了重要作用,，為進(jìn)一步闡明KSHV潛伏感染機(jī)制和針對(duì)KSHV持續(xù)感染的臨床藥物篩選提供線索。
該項(xiàng)研究是在藍(lán)柯研究員指導(dǎo)下,，由博士研究生何之恒,、劉云華、梁德光,、王卓等完成的,。
該研究得到國(guó)家自然科學(xué)基金、中國(guó)科學(xué)院“百人計(jì)劃”和賽諾菲-安萬(wàn)特-中科院上海生命科學(xué)研究院優(yōu)秀青年人才基金項(xiàng)目的資助,。（生物谷Bioon.com）
Figure. GST binding assay, co-immunoprecipitation and immunofluorescence indicate that TLE2 interacts with RTA in vitro and in vivo
生物谷推薦原始出處：
J. Virol. doi:10.1128/JVI.01984-09
Cellular corepressor TLE2 inhibits replication-and-transcription-activator-mediated transactivation and lytic reactivation of Kaposi's sarcoma-associated herpesvirus
Zhiheng He, Yunhua Liu, Deguang Liang, Zhuo Wang, Erle S. Robertson, and Ke Lan*
Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai institutes for biological sciences, Chinese Academy of Sciences, 225 South Chongqing Road, Shanghai 200025, The People's Republic of China; Department of Microbiology and The Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, 201E Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104, USA
Replication and transcription activator (RTA) encoded by ORF50 of Kaposi's sarcoma-associated herpesvirus (KSHV) is essential and sufficient to initiate lytic reactivation. RTA activates its target genes through direct binding with high affinity to its responsive elements or interaction with cellular factors, such as RBP-J, Ap-1, C/EBP- and Oct-1. In this study, we identified transducin-like enhancer of split 2 (TLE2) as a novel RTA binding protein by using yeast two hybrid screening of a human spleen cDNA library. The interaction between TLE2 and RTA was confirmed by GST binding and co-immunoprecipitation assays. Immunofluorescence analysis showed that TLE2 and RTA were co-localized in the same nuclear compartment in KSHV-infected cells. This interaction recruited TLE2 to RTA bound to its recognition sites on DNA, and repressed RTA auto-activation and transactivation activity. Moreover, TLE2 also inhibited the induction of lytic replication and virion production driven by RTA. We further showed that the Q, SP and WDR domains of TLE2 and the Pro-rich domain of RTA were essential for this interaction. RBP-J has been shown previously to bind to the same Pro-rich domain of RTA, and this binding can be subject to competition by TLE2. In addition, TLE2 can form a complex with RTA to access the cognate DNA sequence of RRE (RTA responsive element) at different promoters. Intriguingly, the transcription level of TLE2 could be upregulated by RTA during the lytic reactivation process. In conclusion, we identified a new RTA binding protein, TLE2, and demonstrated that TLE2 inhibited replication and transactivation mediated by RTA. This provides another potentially important mechanism for maintenance of KSHV viral latency through interaction with a host protein.
