人类T细胞白血病病毒1型（HTLV-1）是一种致癌逆转录病毒，导致成人T细胞白血病/淋巴瘤（ATL）。HTLV-1编码的Tax蛋白可以激活病毒长期重复序列（LTR）的转录。通过与Tax结合，多个辅因子参与调控HTLV-1转录。在ATL细胞中，是Hippo信号通路的关键效应物是Yes-相应蛋白（YAP），其水平升高且活化。本研究报告了YAP蛋白通过抑制Tax对HTLV-1 5' LTR的激活而不是3' LTR的激活。当YAP耗竭时，Tax对5' LTR的激活增强。此外，过表达YAP抑制了HTLV-1正链病毒基因的表达和病毒颗粒产量，而RNA干扰抑制YAP则增加了HTLV-1蛋白的表达。作为YAP介导的病毒转录抑制机制，我们发现YAP与Tax相互作用，并阻断了Tax与p300的结合。最终导致Tax无法被招募到HTLV-1 5' LTR中的Tax响应元件上。综上所述，我们的结果表明YAP在Tax激活HTLV-1转录中具有负调控功能。它可能通过足够的转录抑制维持寄主细胞中HTLV-1的持续感染和长期潜伏。© 2023 Wiley Periodicals LLC.

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.© 2023 Wiley Periodicals LLC.