A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection.
A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection.
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DOI：
10.1371/journal.ppat.1007179
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发表时间：
2018-07
期刊：
影响因子：
6.7
通讯作者：
Kenney SC
中科院分区：
文献类型：
--
作者：
Bristol JA;Djavadian R;Albright ER;Coleman CB;Ohashi M;Hayes M;Romero-Masters JC;Barlow EA;Farrell PJ;Rochford R;Kalejta RF;Johannsen EC;Kenney SC
潜伏性EB病毒（EBV）感染有助于B细胞和上皮细胞恶性肿瘤。然而，裂解性EBV感染是否也有助于肿瘤尚不清楚，尽管疟疾感染和伯基特淋巴瘤（BL）之间的关联可能涉及过度裂解性EBV复制。控制裂解性EBV再活化的病毒启动子（Zp）的特定变体相对于其在非恶性组织中的频率在EBV阳性鼻咽癌和AIDS相关淋巴瘤中过度表达。迄今为止，尚未发现原型Zp（Zp-P）和癌症相关变体（Zp-V3）之间的功能差异。在这里，我们表明，Zp-V3和Zp-P启动子之间的单核苷酸差异创建了一个结合位点的细胞转录因子，NFATc 1，在Zp-V3（但不是Zp-P）的变体，并大大提高Zp的活性和裂解病毒的再激活响应NFATc 1诱导的刺激，如B细胞受体激活和离子霉素。此外，我们证明，在完整的EBV B95.8株基因组的背景下，恢复这种NFATc 1基序的Zp-P变体大大增强了裂解病毒的再激活响应NFATc 1激活剂，离子霉素，这种效果被NFAT抑制剂，环孢素，以及NFATc 1 siRNA阻断。我们还表明，Zp-V3变异体在EBV阳性BL和胃癌中过度表达，并且在来自妊娠期间患有疟疾的肯尼亚母亲的EBV感染的母乳的EBV转化的B细胞系中过度表达。这些结果表明，Zp-V3增强了EBV对生理相关刺激的裂解性再活化，并表明裂解性感染的增加可能导致该变体在EBV相关恶性肿瘤中的患病率增加。过量的裂解性EBV感染是否会增加EBV诱导的癌症的风险尚不清楚。据报道，驱动介导裂解性病毒再活化的EBV立即早期BZLF 1（Z）蛋白表达的病毒启动子的特定变体（Zp-V3）在某些EBV阳性恶性肿瘤中过度表达（相对于启动子的原型Zp-P形式），但尚未报道两种启动子变体之间的功能差异。在这里，我们表明，恶性相关的Zp-V3变体（但不是Zp-P变体）包含一个结合位点的细胞NFATc 1（核因子活化T细胞c1）转录因子，使其被激活NFATc 1诱导刺激，如B细胞受体刺激。此外，我们证明，恢复这种NFATc 1基序的Zp-P变异体的背景下，完整的EBV基因组大大增强裂解病毒的再激活响应NFATc 1诱导的刺激。我们还发现，Zp-V3变异体在EBV阳性伯基特淋巴瘤和胃癌中过度表达，并且在由妊娠期间患有疟疾的肯尼亚母亲的EBV感染的母乳转化的淋巴母细胞系中过度表达。这些发现表明，Zp-V3版本的EBV BZLF 1启动子通过增加裂解性EBV感染而增加EBV诱导的恶性肿瘤的可能性。
Latent Epstein-Barr virus (EBV) infection contributes to both B-cell and epithelial-cell malignancies. However, whether lytic EBV infection also contributes to tumors is unclear, although the association between malaria infection and Burkitt lymphomas (BLs) may involve excessive lytic EBV replication. A particular variant of the viral promoter (Zp) that controls lytic EBV reactivation is over-represented, relative to its frequency in non-malignant tissue, in EBV-positive nasopharyngeal carcinomas and AIDS-related lymphomas. To date, no functional differences between the prototype Zp (Zp-P) and the cancer-associated variant (Zp-V3) have been identified. Here we show that a single nucleotide difference between the Zp-V3 and Zp-P promoters creates a binding site for the cellular transcription factor, NFATc1, in the Zp-V3 (but not Zp-P) variant, and greatly enhances Zp activity and lytic viral reactivation in response to NFATc1-inducing stimuli such as B-cell receptor activation and ionomycin. Furthermore, we demonstrate that restoring this NFATc1-motif to the Zp-P variant in the context of the intact EBV B95.8 strain genome greatly enhances lytic viral reactivation in response to the NFATc1-activating agent, ionomycin, and this effect is blocked by the NFAT inhibitory agent, cyclosporine, as well as NFATc1 siRNA. We also show that the Zp-V3 variant is over-represented in EBV-positive BLs and gastric cancers, and in EBV-transformed B-cell lines derived from EBV-infected breast milk of Kenyan mothers that had malaria during pregnancy. These results demonstrate that the Zp-V3 enhances EBV lytic reactivation to physiologically-relevant stimuli, and suggest that increased lytic infection may contribute to the increased prevalence of this variant in EBV-associated malignancies. Whether excessive lytic EBV infection increases the risk of EBV-induced cancers is not clear. A particular variant (Zp-V3) of the viral promoter driving expression of the EBV immediate-early BZLF1 (Z) protein that mediates lytic viral reactivation has been reported to be over-represented (relative to the prototype Zp-P form of the promoter) in certain EBV-positive malignancies, but no functional difference between the two promoter variants has been reported. Here we show that the malignancy-associated Zp-V3 variant (but not the Zp-P variant) contains a binding site for the cellular NFATc1 (nuclear factor of activated T cells c1) transcription factor that allows it to be activated by NFATc1-inducing stimuli such as B-cell receptor stimulation. Furthermore, we demonstrate that restoring this NFATc1-motif to the Zp-P variant in the context of the intact EBV genome greatly enhances lytic viral reactivation in response to the NFATc1-inducing stimuli. We also find that the Zp-V3 variant is over-represented in EBV-positive Burkitt lymphomas and gastric carcinomas, and in lymphoblastoid cell lines transformed by EBV-infected breast milk of Kenyan mothers that had malaria during pregnancy. These findings suggest that the Zp-V3 version of the EBV BZLF1 promoter increases the likelihood of EBV-induced malignancies by increasing lytic EBV infection.
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影响因子：
5.4
作者：
Binné, UK;Amon, W;Farrell, PJ
通讯作者：
Farrell, PJ
影响因子：
6.7
作者：
Bergbauer M;Kalla M;Schmeinck A;Göbel C;Rothbauer U;Eck S;Benet-Pagès A;Strom TM;Hammerschmidt W
通讯作者：
Hammerschmidt W
DOI：
10.1084/jem.20100945
发表时间：
2011-04-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bhattacharyya S;Deb J;Patra AK;Thuy Pham DA;Chen W;Vaeth M;Berberich-Siebelt F;Klein-Hessling S;Lamperti ED;Reifenberg K;Jellusova J;Schweizer A;Nitschke L;Leich E;Rosenwald A;Brunner C;Engelmann S;Bommhardt U;Avots A;Müller MR;Kondo E;Serfling E
通讯作者：
Serfling E
影响因子：
9.4
作者：
Fachiroh, J;Paramita, DK;Middeldorp, JM
通讯作者：
Middeldorp, JM
影响因子：
46.9
作者：
Grillot-Courvalin, C;Goussard, S;Courvalin, P
通讯作者：
Courvalin, P