Department of Otorhinolaryngology: Head and Neck Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
mBio. 2024 Oct 16;15(10):e0181124. doi: 10.1128/mbio.01811-24. Epub 2024 Sep 9.
High-risk human papillomavirus (HPV) oncoproteins inactivate cellular tumor suppressors to reprogram host cell signaling pathways. HPV E7 proteins bind and degrade the tumor suppressor PTPN14, thereby promoting the nuclear localization of the YAP1 oncoprotein and inhibiting keratinocyte differentiation. YAP1 is a transcriptional coactivator that drives epithelial cell stemness and self-renewal. YAP1 activity is inhibited by the highly conserved Hippo pathway, which is frequently inactivated in human cancers. MST1/2 and LATS1/2 kinases form the core of the Hippo kinase cascade. Active LATS1 kinase is phosphorylated on threonine 1079 and inhibits YAP1 by phosphorylating it on amino acids including serine 127. Here, we tested the effect of high-risk (carcinogenic) HPV18 E7 on Hippo pathway activity. We found that either PTPN14 knockout or PTPN14 degradation by HPV18 E7 decreased the phosphorylation of LATS1 T1079 and YAP1 S127 in human keratinocytes and inhibited keratinocyte differentiation. Conversely, PTPN14-dependent differentiation required LATS kinases and certain PPxY motifs in PTPN14. Neither MST1/2 kinases nor the putative PTPN14 phosphatase active sites were required for PTPN14 to promote differentiation. Together, these data support that PTPN14 inactivation or degradation of PTPN14 by HPV18 E7 reduce LATS1 activity, promoting active YAP1 and inhibiting keratinocyte differentiation.IMPORTANCEThe Hippo kinase cascade inhibits YAP1, an oncoprotein and driver of cell stemness and self-renewal. There is mounting evidence that the Hippo pathway is targeted by tumor viruses including human papillomavirus. The high-risk HPV E7 oncoprotein promotes YAP1 nuclear localization and the carcinogenic activity of high-risk HPV E7 requires YAP1 activity. Blocking HPV E7-dependent YAP1 activation could inhibit HPV-mediated carcinogenesis, but the mechanism by which HPV E7 activates YAP1 has not been elucidated. Here we report that by degrading the tumor suppressor PTPN14, HPV18 E7 inhibits LATS1 kinase, reducing inhibitory phosphorylation on YAP1. These data support that an HPV oncoprotein can inhibit Hippo signaling to activate YAP1 and strengthen the link between PTPN14 and Hippo signaling in human epithelial cells.
高危型人乳头瘤病毒（HPV）致癌蛋白使细胞肿瘤抑制物失活，从而重编程宿主细胞信号通路。HPV E7 蛋白与肿瘤抑制物 PTPN14 结合并使其降解，从而促进 YAP1 癌蛋白的核定位，并抑制角质形成细胞分化。YAP1 是一种转录共激活因子，可驱动上皮细胞干性和自我更新。YAP1 的活性受到高度保守的 Hippo 通路的抑制，而 Hippo 通路在人类癌症中经常失活。MST1/2 和 LATS1/2 激酶构成 Hippo 激酶级联的核心。活性 LATS1 激酶在苏氨酸 1079 位磷酸化，并通过磷酸化 YAP1 上包括丝氨酸 127 位在内的氨基酸来抑制 YAP1。在这里，我们检测了高危型（致癌型）HPV18 E7 对 Hippo 通路活性的影响。我们发现，PTPN14 敲除或 HPV18 E7 使 PTPN14 降解均降低了人角质形成细胞中 LATS1 的 T1079 磷酸化和 YAP1 的 S127 磷酸化，并抑制了角质形成细胞分化。相反，PTPN14 依赖的分化需要 LATS 激酶和 PTPN14 中的某些 PPxY 基序。MST1/2 激酶或假定的 PTPN14 磷酸酶活性位点均不是 PTPN14 促进分化所必需的。总之，这些数据表明，HPV18 E7 使 PTPN14 失活或降解会降低 LATS1 的活性，从而促进活性 YAP1 的形成并抑制角质形成细胞分化。重要性 Hippo 激酶级联抑制 YAP1，YAP1 是一种癌蛋白，也是细胞干性和自我更新的驱动因素。越来越多的证据表明，Hippo 通路是包括人乳头瘤病毒在内的肿瘤病毒的靶标。高危型 HPV E7 致癌蛋白促进 YAP1 核定位，高危型 HPV E7 的致癌活性需要 YAP1 活性。阻断 HPV E7 依赖性 YAP1 激活可能会抑制 HPV 介导的癌变，但 HPV E7 激活 YAP1 的机制尚未阐明。在这里，我们报告称，HPV18 E7 通过降解肿瘤抑制物 PTPN14 来抑制 LATS1 激酶，从而减少 YAP1 的抑制性磷酸化。这些数据表明，一种 HPV 致癌蛋白可以抑制 Hippo 信号传导以激活 YAP1，并加强 PTPN14 与人类上皮细胞中 Hippo 信号之间的联系。
