Herpesvirus protein ICP27 switches PML isoform by altering mRNA splicing.
Viruses use alternative splicing to produce a broad series of proteins from small genomes by utilizing the cellular splicing machinery. Since viruses use cellular RNA binding proteins for viral RNA processing, it is presumable that the splicing of cellular pre-mRNAs is affected by viral infection. Here, we showed that herpes simplex virus type 2 (HSV-2) modifies the expression of promyelocytic leukemia (PML) isoforms by altering pre-mRNA splicing. Using a newly developed virus-sensitive splicing reporter, we identified the viral protein ICP27 as an alternative splicing regulator of PML isoforms. ICP27 was found to bind preferentially to PML pre-mRNA and directly inhibit the removal of PML intron 7a in vitro. Moreover, we demonstrated that ICP27 functions as a splicing silencer at the 3' splice site of the PML intron 7a. The switching of PML isoform from PML-II to PML-V as induced by ICP27 affected HSV-2 replication, suggesting that the viral protein modulates the splicing code of cellular pre-mRNA(s) governing virus propagation.
Nojima
Takayuki
T
Department of Functional Genomics, Laboratory of Gene Expression, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo.
Oshiro-Ideue
Takako
T
Nakanoya
Hiroto
H
Kawamura
Hidenobu
H
Morimoto
Tomomi
T
Kawaguchi
Yasushi
Y
Kataoka
Naoyuki
N
Hagiwara
Masatoshi
M
D002460:Cell Line; D017930:Genes, Reporter; D018258:Herpesvirus 2, Human; D006801:Humans; D007438:Introns; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D012322:RNA Precursors / Q000378:metabolism; D022821:RNA Splice Sites; D012326:RNA Splicing; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D012322:RNA Precursors; D022821:RNA Splice Sites; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; C070576:PML protein, human; D012313:RNA