Institute of Technology, University of Tartu, Tartu, Estonia.
J Virol. 2021 Jun 10;95(13):e0025121. doi: 10.1128/JVI.00251-21.
Several types of widespread human papillomaviruses (HPVs) may induce the transformation of infected cells, provoking the development of neoplasms. Two main genera of HPVs are classified as mucosatropic alphapapillomaviruses and cutaneotropic betapapillomaviruses (α- and β-HPVs, respectively), and they both include high-risk cancer-associated species. The absence of antiviral drugs has driven investigations into the details of the molecular mechanisms of the HPV life cycle. HPV replication depends on the viral helicase E1 and the transcription factor E2. Their biological activities are controlled by numerous cellular proteins, including protein kinases. Here, we report that ubiquitously expressed cyclic AMP-dependent protein kinase A (PKA) differentially regulates the replication of α-HPV11, α-HPV18, and β-HPV5. PKA stimulates the replication of both α-HPVs studied but has a more profound effect on the replication of high-risk α-HPV18. However, the replication of β-HPV5 is inhibited by activated PKA in human primary keratinocytes and U2OS cells. We show that the activation of PKA signaling by different pharmacological agents induces the rapid proteasomal degradation of the HPV5 E2 protein, which in turn leads to the downregulation of E2-dependent transcription. In contrast, PKA-stimulated induction of HPV18 replication is the result of the downregulation of the ^ transcript encoding a potent viral transcriptional inhibitor together with the rapid upregulation of E1 and E2 protein levels. Several types of human papillomaviruses (HPVs) are causative agents of various types of epithelial cancers. Here, we report that ubiquitously expressed cyclic AMP-dependent protein kinase A (PKA) differentially regulates the replication of various types of HPVs during the initial amplification and maintenance phases of the viral life cycle. The replication of the skin cancer-related pathogen HPV5 is suppressed, whereas the replication of the cervical cancer-associated pathogen HPV18 is activated, in response to elevated PKA activity. To inhibit HPV5 replication, PKA targets the viral transcriptional activator E2, inducing its rapid proteasomal degradation. PKA-dependent stimulation of HPV18 replication relies on the downregulation of another gene product, ^, which encodes a potent transcriptional repressor. Our findings highlight, for the first time, protein kinase-related mechanistic differences in the regulation of the replication of mucosal and cutaneous HPV types.
几种常见的人类乳头瘤病毒（HPV）可能会导致受感染细胞发生转化，引发肿瘤的发生。HPV 可分为黏膜嗜性的 α 型乳头瘤病毒和皮肤嗜性的 β 型乳头瘤病毒（分别为 α-HPV 和 β-HPV），这两种类型均包含与癌症相关的高危型 HPV。由于缺乏抗病毒药物，人们对 HPV 生命周期的分子机制进行了详细的研究。HPV 的复制依赖于病毒解旋酶 E1 和转录因子 E2。它们的生物学活性受到包括蛋白激酶在内的多种细胞蛋白的控制。在这里，我们报告普遍表达的环磷酸腺苷依赖性蛋白激酶 A（PKA）可差异调节 α-HPV11、α-HPV18 和 β-HPV5 的复制。PKA 可刺激两种研究的 α-HPV 的复制，但对高危型 α-HPV18 的复制影响更显著。然而，在人原代角质形成细胞和 U2OS 细胞中，激活的 PKA 会抑制 β-HPV5 的复制。我们表明，不同药理学试剂激活 PKA 信号会导致 HPV5 E2 蛋白的快速蛋白酶体降解，从而导致 E2 依赖性转录下调。相反，PKA 刺激 HPV18 复制的诱导是由于编码一种有效的病毒转录抑制剂的^转录物下调，以及 E1 和 E2 蛋白水平的快速上调所致。几种类型的人类乳头瘤病毒（HPV）是各种上皮癌的病原体。在这里，我们报告普遍表达的环磷酸腺苷依赖性蛋白激酶 A（PKA）在 HPV 生命周期的初始扩增和维持阶段，可差异调节各种类型 HPV 的复制。皮肤癌相关病原体 HPV5 的复制受到抑制，而宫颈癌相关病原体 HPV18 的复制被激活，这是对 PKA 活性升高的反应。为了抑制 HPV5 的复制，PKA 靶向病毒转录激活因子 E2，诱导其快速蛋白酶体降解。PKA 依赖性刺激 HPV18 复制依赖于另一个基因产物^的下调，该基因产物编码一种有效的转录抑制剂。我们的研究结果首次强调了黏膜型和皮肤型 HPV 复制调节中与蛋白激酶相关的机制差异。
