人類巨細胞病毒(Human cytomegalovirus)是一種很盛行的皰疹病毒，其中迅早期蛋白質IE2(Immediate-early protein 2)是一種關鍵的調控性蛋白質。本論文研究發現IE2可能藉由影響宿主細胞中泛用的共同轉錄調控因子而達到調控基因轉錄之效果。
許多病毒蛋白以細胞中的組蛋白乙醯基轉移酵素（histone acetyltransferase）為調控的目標致發展出疾病。人類巨細胞病毒的迅早期蛋白質IE2 可藉由和腫瘤抑制因子p53 結合而抑制其功能，但是其中的機制仍然不清楚。我們發現IE2能與p53的共同活化因子p300/CBP結合而抑制其乙醯基轉移酵素的活性，並可同時阻止p53及組蛋白的乙醯化。更進一步的實驗結果顯示IE2的1~98之氨基酸片段即具有抑制p300/CBP的能力。進一步以細胞實驗發現p53下游基因啟動子（promoter）的p53結合區域會受到IE2加入之影響而使得該區域的p53以及乙醯化組蛋白的量減少，但反應中使用缺乏組蛋白乙醯基轉移酵素抑制區域(HAT inhibition domain)之IE2則無此能力。進一步將p53序列中能乙醯化之氨基酸位點突變，結果發現IE2仍然能減少點突變之p53的轉錄及和DNA結合活性，顯示IE2抑制p53的活性可能和p53的乙醯化無關，但可能藉由調控組蛋白之乙醯化已達到抑制p53的目的。本研究亦發現只有野生型IE2具有抗細胞凋亡的能力。綜合而言，本研究發現IE2能負向調控p53之活性，係經由抑制p53之共同活化因子p300/CBP所引起之組蛋白乙醯化造成，因此IE2可能具有致癌性。
IE2在控制病毒複製過程扮演重要的角色，為進入爆裂期(lytic cycle)，HCMV 需要viral major immediate-early promoter (MIEP) 的完全活化，其活性在in vitro狀況已證實會被IE2自動抑制，但是相關機制尚未明瞭、是否具特殊生理意義亦不清楚。本研究首先證明IE2會藉由吸引重要的共同調節因子到MIEP而導致染色質的結構轉變，此過程會發生在HCMV 感染細胞的潛伏期及爆裂期。在non-permissive 的細胞中IE2可與MIEP結合，並造成MIEP上的crs (cis-repression sequence)周遭區域的組蛋白之去乙醯化。在被HCMV感染的潛溶期細胞中，IE2 則會結合到crs 並吸引Histon H3K9的甲基轉移酵素和Mi-2 共同抑制因子複合體，此時IE2扮演區域性DNA甲基化的媒介。相反的，IE2在HCMV感染的爆裂期細胞中能吸引共同活化因子 PCAF到MIEP。本發現顯示IE2能吸引特定的染色質共同調節因子以調節HCMV主要的promoter,因此IE2的表現及功能在HCMV的潛伏期和活化期均扮演重要的角色。

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Human cytomegalovirus (HCMV) is a kind of high prevalence herpesvirus, and the immediate-early protein 2 (IE2) is one of the critical regulatory viral proteins of HCMV. In this study, we demonstrate that IE2 regulates transcriptional process by affecting common transcription cofactors on both cellular and viral promoters.

Various viral proteins can target cellular transcriptional regulator to modulate transcription in which histone acetyltransferases (HATs) serve as a key common target for viral proteins. The immediate-early 2 protein (IE2) of human cytomegalovirus (HCMV) interacts with the tumor suppressor p53, and downregulates its functions by unknown mechanisms. In our study, we demonstrate that IE2 influences the p53 functions through inhibiting the acetyltransferase activity of the p53 coactivators, p300 and CREB-binding protein (CBP), which in turn inhibits functions of both histones and p53. IE2 can directly interact with p300 and CBP, and the minimal HAT inactivation region on IE2 contains the N-terminal 98 amino acids. It also decreases the level of local acetylated histones on p53-dependent promoters, such that the in vivo DNA binding ability of p53 is influenced. However, the mutant IE2 proteins that lack the HAT inhibition region do not have similar function. In addition, the p53 acetylation site mutant, K320/373/382R, retains both DNA binding and promoter transactivation activity in vivo and these effects are suppressed by IE2 as well. On the other hand, we have also observed that only wild-type IE2 has an antiapoptotic effect. Together with these finding, our results imply that HCMV IE2 represses p53-dependent gene activation through inhibiting p300/CBP-mediated local histone acetylation and that IE2 may have oncogenic activity.

In addition, IE2 plays an important role in viral replication. To enter lytic cycle, HCMV requires full activation of the HCMV major immediate-early promoter (MIEP) whose activity is shown to be autorepressed by the IE2 in vitro, with unknown mechanism and physiological significance. Here we demonstrate that IE2 mediates local chromatin structure remodeling via recruitment of distinct coregulators to MIEP in HCMV latently or lytically infected cells. IE2-binding to MIEP in HCMV non-permissive cells results in inhibition of the MIEP activity in a cis-repression sequence (crs)- and histone deacetylase-dependent manner. In cells latently infected by HCMV, IE2 binding to crs recruits histone 3 K9 methylatransferases as well as the Mi-2 corepressor complex which involves distinct activities such as ATP-dependent chromatin remodeling, histone deacetylation and binding to methylated CpG. Consistently, IE2 also mediates local DNA methylation. In contrast, IE2 recruits coactivator PCAF to MIEP in HCMV lytically infected cells. Taken together, these studies indicate that IE2 recruits specific chromatin coregulators to regulate the activity of MIEP and this may potentially play an important role to determinate whether HCMV enter latency or lytic cycle.

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