Institute of Virology, University of Cologne, Faculty of Medicine and University Hospital of Cologne,Fürst-Pückler-Strasse 56, 50935 Cologne, Germany.
ViiV Healthcare, Prinzregentenplatz 9, 81675 Munich, Germany.
Cells. 2019 Mar 14;8(3):244. doi: 10.3390/cells8030244.
Human papillomaviruses (HPV) replicate their DNA in the suprabasal layer of the infected mucosa or skin. In order to create a suitable environment for vegetative viral DNA replication HPV delay differentiation and sustain keratinocyte proliferation that can lead to hyperplasia. The mechanism underlying cell growth stimulation is not well characterized. Here, we show that the E6 oncoprotein of the βHPV type 8 (HPV8), which infects the cutaneous skin and is associated with skin cancer in Epidermodysplasia verruciformis patients and immunosuppressed organ transplant recipients, binds to the protein tyrosine phosphatase H1 (PTPH1), which resulted in increased protein expression and phosphatase activity of PTPH1. Suppression of PTPH1 in immortalized keratinocytes reduced cell proliferation as well as the level of epidermal growth factor receptor (EGFR). Furthermore, we report that HPV8E6 expressing keratinocytes have increased level of active, GTP-bound Ras. This effect was independent of PTPH1. Therefore, HPV8E6-mediated targeting of PTPH1 might result in higher level of EGFR and enhanced keratinocyte proliferation. The HPV8E6-mediated stimulation of Ras may be an additional step to induce cell growth. Our results provide novel insights into the mechanism how βHPVE6 proteins support proliferation of infected keratinocytes, thus creating an environment with increased risk of development of skin cancer particularly upon UV-induced DNA mutations.
人乳头瘤病毒 (HPV) 在感染的黏膜或皮肤的基底层复制其 DNA。为了为营养型病毒 DNA 复制创造合适的环境，HPV 会延迟分化并维持角质形成细胞的增殖，从而导致增生。细胞生长刺激的机制尚未得到很好的描述。在这里，我们展示了 βHPV 型 8（HPV8）的 E6 癌蛋白，它感染皮肤，与疣状表皮发育不良患者和免疫抑制器官移植受者的皮肤癌有关，与蛋白酪氨酸磷酸酶 H1（PTPH1）结合，导致 PTPH1 的蛋白表达和磷酸酶活性增加。在永生化角质形成细胞中抑制 PTPH1 会降低细胞增殖以及表皮生长因子受体 (EGFR) 的水平。此外，我们报告说表达 HPV8E6 的角质形成细胞具有更高水平的活性、GTP 结合的 Ras。这种效应独立于 PTPH1。因此，HPV8E6 介导的 PTPH1 靶向可能导致更高水平的 EGFR 和增强的角质形成细胞增殖。HPV8E6 介导的 Ras 刺激可能是诱导细胞生长的另一个步骤。我们的研究结果为 βHPVE6 蛋白如何支持感染的角质形成细胞增殖提供了新的见解，从而在 UV 诱导的 DNA 突变的情况下，增加了皮肤癌发展的风险。
