The Transcriptional Cofactor VGLL1 Drives Transcription of Human Papillomavirus Early Genes via TEAD1
The Transcriptional Cofactor VGLL1 Drives Transcription of Human Papillomavirus Early Genes via TEAD1
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DOI：
10.1128/jvi.01945-19
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发表时间：
2020-05-01
影响因子：
5.4
通讯作者：
Kukimoto, Iwao
中科院分区：
文献类型：
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作者：
Mori, Seiichiro;Takeuchi, Takamasa;Kukimoto, Iwao
TEAD家族的转录因子需要相关的辅因子来诱导基因表达。已知TEAD 1激活人乳头瘤病毒（HPV）的早期启动子，但TEAD 1介导的HPV启动子（包括其相关辅因子）反式激活的确切机制尚未探索。在这里，我们揭示了VGLL 1，TEAD相互作用的辅因子，有助于HPV早期基因表达。VGLL 1和/或TEAD 1的敲低导致人宫颈角质形成细胞和宫颈癌细胞系中病毒早期基因表达的减少。我们通过体外DNA下拉试验在HPV 16长控制区（LCR）中鉴定了11个TEAD 1靶位点;其中8个位点在荧光素酶报告基因试验中促进了早期启动子的转录激活。VGLL 1通过其与TEAD 1的相互作用在体外和体内与HPV 16 LCR结合。此外，将HPV 16和HPV 18全基因组引入原代人角质形成细胞导致VGLL 1水平增加，部分原因是TEAD上调。这些结果表明，多个VGLL 1/TEAD 1复合物被招募到LCR，以支持HPV早期基因的有效转录。重要的是，虽然一些转录因子已被报道参与HPV基因的表达，很少有人知道的辅助因子，支持HPV转录。在这项研究中，我们证明了转录辅因子VGLL 1在HPV早期基因表达中起着重要作用，这取决于它与转录因子TEAD 1的关系。尽管TEAD 1在多种组织中普遍表达，但VGLL 1显示组织特异性表达，并涉及上皮谱系组织的发育和分化，其中HPV基因表达发生。我们的研究结果表明，VGLL 1可能有助于HPV基因表达的上皮特异性，为调节HPV感染的机制提供了新的见解。此外，VGLL 1对宫颈癌细胞的生长也至关重要，可能是HPV相关癌症的新治疗靶点。
The TEAD family of transcription factors requires associating cofactors to induce gene expression. TEAD1 is known to activate the early promoter of human papillomavirus (HPV), but the precise mechanisms of TEAD1-mediated transactivation of the HPV promoter, including its relevant cofactors, remain unexplored. Here, we reveal that VGLL1, a TEAD-interacting cofactor, contributes to HPV early gene expression. Knockdown of VGLL1 and/or TEAD1 led to a decrease in viral early gene expression in human cervical keratinocytes and cervical cancer cell lines. We identified 11 TEAD1 target sites in the HPV16 long control region (LCR) by in vitro DNA pulldown assays; 8 of these sites contributed to the transcriptional activation of the early promoter in luciferase reporter assays. VGLL1 bound to the HPV16 LCR via its interaction with TEAD1 both in vitro and in vivo. Furthermore, introducing HPV16 and HPV18 whole genomes into primary human keratinocytes led to increased levels of VGLL1, due in part to the upregulation of TEADs. These results suggest that multiple VGLL1/TEAD1 complexes are recruited to the LCR to support the efficient transcription of HPV early genes.IMPORTANCE Although a number of transcription factors have been reported to be involved in HPV gene expression, little is known about the cofactors that support HPV transcription. In this study, we demonstrate that the transcriptional cofactor VGLL1 plays a prominent role in HPV early gene expression, dependent on its association with the transcription factor TEAD1. Whereas TEAD1 is ubiquitously expressed in a variety of tissues, VGLL1 displays tissue-specific expression and is implicated in the development and differentiation of epithelial lineage tissues, where HPV gene expression occurs. Our results suggest that VGLL1 may contribute to the epithelial specificity of HPV gene expression, providing new insights into the mechanisms that regulate HPV infection. Further, VGLL1 is also critical for the growth of cervical cancer cells and may represent a novel therapeutic target for HPV-associated cancers.