Several lines of evidence indicate that cutaneous human papillomavirus (HPV) types belonging to the beta genus of the HPV phylogenetic tree synergize with UV radiation in the development of skin cancer. Accordingly, the E6 and E7 oncoproteins from some beta HPV types are able to deregulate pathways related to immune response and cellular transformation. Toll-like receptor 9 (TLR9), in addition to playing a role in innate immunity, has been shown to be involved in the cellular stress response. Using primary human keratinocytes as experimental models, we have shown that UV irradiation (and other cellular stresses) activates TLR9 expression. This event is closely linked to p53 activation. Silencing the expression of p53 or deleting its encoding gene affected the activation of TLR9 expression after UV irradiation. Using various strategies, we have also shown that the transcription factors p53 and c-Jun are recruited onto a specific region of the TLR9 promoter after UV irradiation. Importantly, the E6 and E7 oncoproteins from beta HPV38, by inducing the accumulation of the p53 antagonist ΔNp73α, prevent the UV-mediated recruitment of these transcription factors onto the TLR9 promoter, with subsequent impairment of TLR9 gene expression. This study provides new insight into the mechanism that mediates TLR9 upregulation in response to cellular stresses. In addition, we show that HPV38 E6 and E7 are able to interfere with this mechanism, providing another explanation for the possible cooperation of beta HPV types with UV radiation in skin carcinogenesis.

IMPORTANCE Beta HPV types have been suggested to act as cofactors in UV-induced skin carcinogenesis by altering several cellular mechanisms activated by UV radiation. We show that the expression of TLR9, a sensor of damage-associated molecular patterns produced during cellular stress, is activated by UV radiation in primary human keratinocytes (PHKs). Two transcription factors known to be activated by UV radiation, p53 and c-Jun, play key roles in UV-activated TLR9 expression. The E6 and E7 oncoproteins from beta HPV38 strongly inhibit UV-activated TLR9 expression by preventing the recruitment of p53 and c-Jun to the TLR9 promoter. Our findings provide additional support for the role that beta HPV types play in skin carcinogenesis by preventing activation of specific pathways upon exposure of PHKs to UV radiation.

多项证据表明，属于 HPV 系统发育树 β 属的皮肤人乳头瘤病毒 (HPV) 类型与紫外线辐射在皮肤癌的发展中具有协同作用。因此，来自某些 β HPV 类型的 E6 和 E7 癌蛋白能够解除与免疫反应和细胞转化相关途径的调节。 Toll 样受体 9 (TLR9​​) 除了在先天免疫中发挥作用外，还被证明参与细胞应激反应。使用原代人角质形成细胞作为实验模型，我们发现紫外线照射（和其他细胞应激）可激活 TLR9 表达。该事件与 p53 激活密切相关。沉默p53的表达或删除其编码基因会影响UV照射后TLR9表达的激活。使用各种策略，我们还表明转录因子 p53 和 c-Jun 在紫外线照射后被招募到 TLR9 启动子的特定区域。重要的是，来自 β HPV38 的 E6 和 E7 癌蛋白通过诱导 p53 拮抗剂 ΔNp73α 的积累，阻止紫外线介导的这些转录因子募集到 TLR9 启动子上，从而损害 TLR9 基因表达。这项研究为介导 TLR9 上调以应对细胞应激的机制提供了新的见解。此外，我们还发现 HPV38 E6 和 E7 能够干扰这一机制，这为 β HPV 类型与紫外线辐射在皮肤癌发生中可能的协同作用提供了另一种解释。

重要性β HPV 类型被认为通过改变紫外线辐射激活的多种细胞机制，在紫外线诱导的皮肤癌发生中充当辅助因子。我们发现，TLR9（细胞应激期间产生的损伤相关分子模式的传感器）的表达被原代人角质形成细胞（PHK）中的紫外线辐射激活。已知可被紫外线辐射激活的两种转录因子 p53 和 c-Jun 在紫外线激活的 TLR9 表达中发挥着关键作用。来自 beta HPV38 的 E6 和 E7 癌蛋白通过阻止 p53 和 c-Jun 募集至 TLR9 启动子来强烈抑制紫外线激活的 TLR9 表达。我们的研究结果为 β HPV 类型在皮肤癌发生中发挥的作用提供了额外的支持，通过阻止 PHK 暴露于紫外线辐射时特定途径的激活。