β类人乳头瘤病毒（HPVs）感染引起表皮增生性皮损。对于罕见的遗传性皮肤病患者——表皮发育不良疣状纤维症，这些皮损可以发展为皮肤鳞状细胞癌（cSCCs）。β-HPVs可能也是慢性免疫抑制者cSCC发展的潜在因素。尽管这些病毒的患病率和疾病相关性很高，但它们的研究还不如与癌症相关的高风险α类乳头瘤病毒（HPVs）所深入。HPV相关病变的特征是有明显的基底样、分裂活跃、低分化的病毒感染细胞扩增，这些细胞携带病毒基因。这反映出HPVs能够抑制上皮细胞的分化，这一能力可能是通过在基底样上皮细胞中建立和维持长期病毒感染而驱动的。令人惊讶的是，β-HPVs通过与α类HPVs靶向不同的细胞效应器来实现这一点。此前报道称，HPV8 E6蛋白能够通过抑制Notch和转化生长因子β信号来抑制上皮细胞分化。在这里，我们报道了HPV8 E6蛋白可以通过激活“转录增强关联结构域”（TEAD）转录程序来绕过Hippo信号，抑制角质细胞分化标记物的表达。此外，我们还确定了HPV8 E6可以通过与β-连环蛋白相关转录共激活因子BCL9L结合干扰Wnt信号的基因表达程序，这也有助于抑制上皮细胞分化标记物的表达。因此，HPV8 E6蛋白已发展出一系列非常丰富的机制来逆转受感染上皮细胞的分化程序。意义重大的是，人乳头瘤病毒（HPVs）感染基底上皮细胞并导致基底样、增殖性细胞显著扩展。这反映了乳头瘤病毒延迟角质细胞分化的能力，从而保持了持续感染细胞的一些基底细胞的特征。这可能使乳头瘤病毒能够在鳞状上皮组织中建立和维持长期感染。之前的研究揭示了β-HPV8 E6蛋白抑制Notch和转化生长因子β信号的能力对这一活性的重要贡献。在这里，我们提供了证据表明HPV8 E6也逆转Hippo和Wnt信号，而且这些活动也有助于抑制角质细胞分化。

Infections with β-genus human papillomaviruses (HPVs) cause hyperplastic cutaneous lesions. In individuals with the rare hereditary skin disease, epidermodysplasia verruciformis, such lesions can progress to cutaneous squamous cell carcinomas (cSCCs). β-HPV infections may also underlie cSCC development in chronically immunosuppressed individuals. Despite their prevalence and disease association, these viruses are not as well studied as the cancer-associated high-risk α-genus HPVs. HPV-associated lesions are characterized by a marked expansion of dividing, basal-like, poorly differentiated viral cells that contain viral genomes. This reflects the ability of HPVs to inhibit epithelial cell differentiation which is likely driven by the need to establish and maintain long-term viral infections in basal-like epithelial cells. Remarkably, the β-HPVs accomplish this by targeting different cellular effectors than the α-genus HPVs. It was previously reported that the HPV8 E6 protein restrains epithelial cell differentiation by inhibiting Notch and transforming growth factor β signaling. Here, we report that the HPV8 E6 protein can subvert Hippo signaling by activating Transcriptional Enhanced Associate Domain (TEAD) transcriptional programs that inhibit the expression of keratinocyte differentiation markers. Moreover, we determined that HPV8 E6 can interfere with gene expression programs triggered by Wnt signaling by binding to the β-catenin-associated transcriptional co-activator B-cell CLL/lymphoma 9-like(BCL9L) and that this also serves to restrain the expression of epithelial differentiation markers. Hence, the HPV8 E6 protein has evolved a remarkably large array of mechanisms to subvert the differentiation program of the infected epithelial cells. IMPORTANCE Human papillomaviruses (HPVs) infect basal epithelial cells and cause a dramatic expansion of basal-like, proliferative cells. This reflects the ability of papillomaviruses to delay keratinocyte differentiation, thereby maintaining aspects of the basal cell identity of persistently infected cells. This may enable papillomaviruses to establish and maintain long-term infections in squamous epithelial tissues. Previous work has revealed that the ability of β-HPV8 E6 protein to inhibit Notch and transforming growth factor β signaling importantly contributes to this activity. Here, we present evidence that HPV8 E6 also subverts Hippo and Wnt signaling and that these activities also aid in restraining keratinocyte differentiation.