Several types of widespread human papillomaviruses (HPVs) may induce transformation of infected cells, provoking the development of neoplasms. Two main genera of HPVs are classified as mucosatropic α and cutaneotropic β HPVs, 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 viral helicase E1 and 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, replication of β HPV5 is inhibited by activated PKA in human primary keratinocytes and U2OS cells. We show that activation of PKA signaling by different pharmacological agents induces 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 E8^E2 transcript coding a potent viral transcriptional inhibitor together with rapid upregulation of E1 and E2 protein levels.
IMPORTANCE
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. Replication of the skin cancer-related pathogen HPV5 is suppressed, whereas replication of the cervical cancer-associated 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 E2 gene product, E8^E2, 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.
Mitoxantrone in combination with an inhibitor of DNA-dependent protein kinase: a potential therapy for high risk B-cell chronic lymphocytic leukaemia
