Herpes simplex virus 1 DNA polymerase processivity factor UL42 inhibits TNF-α-induced NF-κB activation by interacting with p65/RelA and p50/NF-κB1

Med Microbiol Immunol. 2013 Aug;202(4):313-25. doi: 10.1007/s00430-013-0295-0. Epub 2013 May 1.

Abstract

Herpes simplex virus 1 (HSV-1) is the archetypal member of the alphaherpesvirus with a large genome encoding over 80 viral proteins, many of which are involved in virus-host interactions and show immune modulatory capabilities. In this study, we demonstrated that the HSV-1 UL42 protein, a DNA polymerase processivity factor, was a novel antagonism of the canonical NF-κB signaling pathway. UL42 was shown to significantly suppress TNF-α mediated NF-κB activation. Co-immunoprecipitation experiment revealed that UL42 bound to the NF-κB subunits p65 and p50. Fluorescence microscopy demonstrated that UL42 abolished nuclear translocation of p65 and p50 upon TNF-α-stimulation. But the inhibiting capacity of UL42 2R/2A (R279A, R280A) and UL42 3R/3A (R113A, R279A and R280A) mutants were less than wild type UL42. Also UL42 bound to the Rel homology domain of the NF-κB subunit p65 and p50. Notably, the N-terminal of UL42 was sufficient to interact with p65 and p50 and abolished NF-κB reporter gene activity. Thus, it was first time we demonstrated that HSV-1 UL42 appeared to prevent NF-κB-dependent gene expression by retaining p65 and p50 in the cytoplasm, and UL42-dependent transcriptional activation were inherently coupled to promote HSV-1 lytic replication, which also may contribute to immune evasion and pathogenesis of HSV-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA-Directed DNA Polymerase / metabolism*
  • Exodeoxyribonucleases / metabolism*
  • Herpesvirus 1, Human / immunology*
  • Host-Pathogen Interactions*
  • Humans
  • Immunoprecipitation
  • Microscopy, Fluorescence
  • NF-kappa B p50 Subunit / antagonists & inhibitors*
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Transport
  • Transcription Factor RelA / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / immunology*
  • Viral Proteins / metabolism*

Substances

  • NF-kappa B p50 Subunit
  • RELA protein, human
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Viral Proteins
  • DNA-Directed DNA Polymerase
  • Exodeoxyribonucleases
  • DNA polymerase, Simplexvirus