期刊
VACCINES
卷 9, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/vaccines9101054
关键词
cyclin-dependent kinase; transcription elongation checkpoint; tegument protein VP16; immediate-early protein; amber codon suppression technology
资金
- Wellcome Trust Investigator Award
- Centre National de Recherche Scientifique
- Ecole Normale Superieure
- Institut National de la Sante et de la Recherche Medicale, France
- Malaysia Ministry of Higher Education and IIUM Malaysia
The HSV-1 protein ICP22 interacts with cellular proteins to inhibit host cell gene expression and promote viral gene expression, affecting elongation of pol II through various checkpoints. ICP22 interacts with elongation regulators to inhibit transcription elongation of cellular genes. The viral activator VP16 competes with ICP22 to deliver elongation factors to viral genes.
The Herpes Simplex Virus (HSV-1) immediate-early protein ICP22 interacts with cellular proteins to inhibit host cell gene expression and promote viral gene expression. ICP22 inhibits phosphorylation of Ser2 of the RNA polymerase II (pol II) carboxyl-terminal domain (CTD) and productive elongation of pol II. Here we show that ICP22 affects elongation of pol II through both the early-elongation checkpoint and the poly(A)-associated elongation checkpoint of a protein-coding gene model. Coimmunoprecipitation assays using tagged ICP22 expressed in human cells and pulldown assays with recombinant ICP22 in vitro coupled with mass spectrometry identify transcription elongation factors, including P-TEFb, additional CTD kinases and the FACT complex as interacting cellular factors. Using a photoreactive amino acid incorporated into ICP22, we found that L191, Y230 and C225 crosslink to both subunits of the FACT complex in cells. Our findings indicate that ICP22 interacts with critical elongation regulators to inhibit transcription elongation of cellular genes, which may be vital for HSV-1 pathogenesis. We also show that the HSV viral activator, VP16, has a region of structural similarity to the ICP22 region that interacts with elongation factors, suggesting a model where VP16 competes with ICP22 to deliver elongation factors to viral genes.
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