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Herpesvirus protein ICP27 switches PML isoform by altering mRNA splicing

Takayuki Nojima1, Takako Oshiro-Ideue, Hiroto Nakanoya

  • 1Department of Functional Genomics, Laboratory of Gene Expression, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo.

Nucleic Acids Research
|September 5, 2009
PubMed

Insights

Herpes simplex virus type 2 (HSV-2) alters cellular pre-mRNA splicing. The viral protein ICP27 acts as a splicing silencer, modifying promyelocytic leukemia (PML) isoform expression and impacting HSV-2 replication.

Area of Science:

  • Molecular Biology
  • Virology
  • Genetics

Background:

  • Viruses leverage host cell machinery, including alternative splicing, to expand their proteomic output from limited genomes.
  • Viral infections can disrupt host cell processes, potentially affecting cellular pre-messenger RNA (pre-mRNA) splicing due to interactions with cellular RNA-binding proteins.

Purpose of the Study:

  • To investigate how herpes simplex virus type 2 (HSV-2) infection influences the splicing of cellular pre-mRNAs.
  • To identify specific viral proteins involved in regulating alternative splicing of cellular genes.
  • To elucidate the mechanism by which viral proteins modulate host cell splicing patterns.

Main Methods:

  • Development and utilization of a novel virus-sensitive splicing reporter system.
  • Identification of viral protein ICP27 as a key regulator of promyelocytic leukemia (PML) isoform splicing.
  • In vitro binding assays to demonstrate ICP27's preferential binding to PML pre-mRNA.
  • Functional analysis of ICP27's role as a splicing silencer at a specific intronic splice site.

Main Results:

  • HSV-2 infection was shown to alter the expression of promyelocytic leukemia (PML) isoforms through modifications in pre-mRNA splicing.
  • The viral protein ICP27 was identified as a direct regulator of PML alternative splicing.
  • ICP27 was observed to bind preferentially to PML pre-mRNA and inhibit the removal of intron 7a.
  • ICP27 functions as a splicing silencer at the 3' splice site of PML intron 7a, leading to a switch from PML-II to PML-V isoforms.
  • This ICP27-induced shift in PML isoforms was found to affect HSV-2 replication.

Conclusions:

  • Herpes simplex virus type 2 ICP27 directly modulates host cell pre-mRNA splicing, specifically targeting PML isoforms.
  • ICP27 acts as a splicing silencer, altering the cellular splicing code to favor specific PML isoforms.
  • The observed changes in PML isoform expression by ICP27 play a role in regulating HSV-2 viral propagation.

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