ICP27 interacts with SRPK1 to mediate HSV splicing inhibition by altering SR protein phosphorylation.
Infection with some viruses can alter cellular mRNA processing to favor viral gene expression. We present evidence that herpes simplex virus 1 (HSV-1) protein ICP27, which contributes to host shut-off by inhibiting pre-mRNA splicing, interacts with essential splicing factors termed SR proteins and affects their phosphorylation. During HSV-1 infection, phosphorylation of several SR proteins was reduced and this correlated with a subnuclear redistribution. Exogenous SR proteins restored splicing in ICP27-inhibited nuclear extracts and SR proteins isolated from HSV-1-infected cells activated splicing in uninfected S100 extracts, indicating that inhibition occurs by a reversible mechanism. Spliceosome assembly was blocked at the pre-spliceosomal complex A stage. Furthermore, we show that ICP27 interacts with SRPK1 and relocalizes it to the nucleus; moreover, SRPK1 activity was altered in the presence of ICP27 in vitro. We propose that ICP27 modifies SRPK1 activity resulting in hypophosphorylation of SR proteins impairing their ability to function in spliceosome assembly.
Sciabica
Kathryn S
KS
Department of Microbiology and Molecular Genetics, University of California, Irvine, CA 92697, USA.
Dai
Qian J
QJ
Sandri-Goldin
Rozanne M
RM
D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012326:RNA Splicing
C057120:ICP27 protein, human herpesvirus 1; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; C087728:SRPK1 protein, human; D017346:Protein Serine-Threonine Kinases