The splicing factor kinase, SR protein kinase 1 (SRPK1) is essential for late events in the human papillomavirus life cycle

Human papillomaviruses (HPV) infect epithelia to cause benign lesions or warts. However, the so-called “high risk” HPVs infecting the anogenital region and the oropharynx can cause precancerous lesions that may progress to malignant tumours. Understanding the HPV life cycle is important to the discovery of novel antiviral therapies. HPV uses cellular splicing to produce the full suite of viral mRNAs. Members of the serine/arginine rich (SR) protein family can positively regulate splicing. SR protein activity and cellular location is regulated by phosphorylation of their serine-arginine domains. SR protein kinases (SRPK) can phosphorylate SR proteins. This licenses their nuclear entry and promotes nuclear splicing together with another SR protein kinase, Clk1. SRPIN340 is a specific inhibitor of SRPK1. It has been reported to inhibit replication of HCV, Sindbis virus and HIV. We show here that SRPIN340 inhibits the expression of the viral replication and transcription factor, E2. Loss of HPV E4 and L1 late proteins was also observed. RNA sequencing showed SRPIN340 treatment resulted in gene expression changes opposite to those induced by HPV16 infection. In particular, the loss of the epithelial barrier was restored. SRPIN340 treatment led to changes in alternative splicing of 935 RNAs and pathway analysis showed a predominance of changes to RNAs encoding proteins involved in chromatin conformation, DNA repair and RNA processing. Short term SRPIN340 treatment (two to three days) was not associated with changes in proliferation or differentiation of keratinocytes. Since SRPK1 controls the E2 viral replication and transcription factor, targeting this kinase, or the phosphorylation events it mediates, could be considered as a therapeutic strategy for HPV16 infection.