The E1circumflexE4 protein of human papillomavirus interacts with the serine-arginine-specific protein kinase SRPK1.
Human papillomavirus (HPV) infections of the squamous epithelium are associated with high-level expression of the E1circumflexE4 protein during the productive phase of infection. However, the precise mechanisms of how E1circumflexE4 contributes to the replication cycle of the virus are poorly understood. Here, we show that the serine-arginine (SR)-specific protein kinase SRPK1 is a novel binding partner of HPV type 1 (HPV1) E1circumflexE4. We map critical residues within an arginine-rich domain of HPV1 E1circumflexE4, and in a region known to facilitate E1circumflexE4 oligomerization, that are requisite for SRPK1 binding. In vitro kinase assays show that SRPK1 binding is associated with phosphorylation of an HPV1 E1circumflexE4 polypeptide and modulates autophosphorylation of the kinase. We show that SRPK1 is sequestered into E4 inclusion bodies in terminally differentiated cells within HPV1 warts and that colocalization between E1circumflexE4 and SRPK1 is not dependent on additional HPV1 factors. Moreover, we also identify SRPK1 binding of E1circumflexE4 proteins of HPV16 and HPV18. Our findings indicate that SRPK1 binding is a conserved function of E1circumflexE4 proteins of diverse virus types. SRPK1 influences important biochemical processes within the cell, including nuclear organization and RNA metabolism. While phosphorylation of HPV1 E4 by SRPK1 may directly influence HPV1 E4 function during the infectious cycle, the modulation and sequestration of SRPK1 by E1circumflexE4 may affect the ability of SRPK1 to phosphorylate its cellular targets, thereby facilitating the productive phase of the HPV replication cycle.
Bell
Ian
I
Cancer Research UK Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, United Kingdom.
Martin
Ashley
A
Roberts
Sally
S
D000595:Amino Acid Sequence; D001120:Arginine / Q000378:metabolism; D002460:Cell Line; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism; D052161:Human papillomavirus 18 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology / Q000821:virology; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
C471608:E1 protein, human papillomavirus type 1; D009856:Oncogene Proteins, Viral; D014764:Viral Proteins; C069119:oncogene protein E4, Human papillomavirus type 16; C056651:oncogene protein E4, human papilloma virus type 1; D012694:Serine; D001120:Arginine; C087728:SRPK1 protein, human; D017346:Protein Serine-Threonine Kinases