Abstract:
Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 encodes Tax protein that activates transcription from viral long terminal repeats (LTR). Multiple cofactors are involved in the regulation of HTLV-1 transcription via association with Tax. Yes-associated protein (YAP), which is the key effector of Hippo pathway, is elevated and activated in ATL cells. In this study, we reported that YAP protein suppressed Tax activation of HTLV-1 5\' LTR but not 3\' LTR. The activation of the 5\' LTR by Tax was potentiated when YAP was depleted. Moreover, overexpression of YAP repressed HTLV-1 plus-strand viral gene expression and virion production, whereas compromising YAP by RNA inference augmented the expression of HTLV-1 protein. As mechanisms of YAP-mediated viral transcription inhibition, we found that YAP interacted with Tax, and prevented the association between Tax and p300. It finally led to the inhibition of recruitment of Tax to the Tax-responsive element in the 5\' LTR of HTLV-1. Taken together, our results demonstrate the negative regulatory function of YAP in Tax activation of HTLV-1 transcription. It may achieve sufficient transcriptional repression to maintain persistent infection and long-term latency of HTLV-1 in the host cells.
摘要:
人T细胞白血病病毒1型(HTLV-1)是一种致癌逆转录病毒,可引起成人T细胞白血病/淋巴瘤(ATL)。HTLV-1编码Tax蛋白,可激活病毒长末端重复序列(LTR)的转录。通过与Tax的关联,多种辅因子参与HTLV-1转录的调节。是相关蛋白(YAP),这是河马途径的关键效应,在ATL细胞中升高并激活。在这项研究中,我们报道YAP蛋白抑制HTLV-15'LTR的税收激活,但不抑制3'LTR。当YAP耗尽时,税收对5'LTR的激活得到了加强。此外,YAP的过表达抑制HTLV-1正链病毒基因的表达和病毒体的产生,而通过RNA推断损害YAP会增加HTLV-1蛋白的表达。作为YAP介导的病毒转录抑制的机制,我们发现YAP和Tax有互动,并阻止了Tax和p300之间的联系。最终导致抑制了HTLV-1的5'LTR中税收响应要素的税收招募。一起来看,我们的结果表明YAP在HTLV-1转录的税收激活中具有负调节功能。它可以实现足够的转录抑制以维持宿主细胞中HTLV-1的持续感染和长期潜伏期。