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MDV-encoded protein kinase US3 phosphorylates WTAP to inhibit transcriptomic m6A modification and cellular protein

Lele Wang1, Wenhui Zhu1, Lele Gong1

  • 1College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou 450046, China.

Veterinary Microbiology
|December 7, 2024
PubMed

Insights

Marek's disease virus US3 protein kinase phosphorylates WTAP, inhibiting m6A modification and protein translation. This study clarifies the molecular mechanisms of US3's role in MDV infection.

Area of Science:

  • Virology
  • Molecular Biology
  • Biochemistry

Background:

  • Marek's disease virus (MDV) US3 is a serine/threonine protein kinase conserved in alpha-herpesviruses.
  • In other viruses, US3 inhibits N6-methyladenosine (m6A) modification by phosphorylating Wilms tumor 1-associated protein (WTAP).
  • The specific function and mechanism of MDV US3-mediated WTAP phosphorylation are not well understood.

Purpose of the Study:

  • To investigate the role and mechanism of MDV US3 in WTAP phosphorylation.
  • To elucidate how US3 affects m6A modification and protein translation during MDV infection.

Main Methods:

  • In vitro and in vivo MDV infection models.
  • Co-immunoprecipitation and immunofluorescence assays to study protein interactions and localization.
  • Site-directed mutagenesis and in vitro kinase assays to identify phosphorylation sites.
  • Analysis of m6A modification levels and protein translation rates.

Main Results:

  • MDV US3 interacts with and co-localizes with WTAP in the nucleus.
  • US3 phosphorylates WTAP at specific serine residues (S273, S305, S314, S375) within its C-terminal domain.
  • This interaction does not affect WTAP stability but significantly inhibits transcriptomic m6A modification.
  • Cellular protein translation is suppressed due to US3-mediated WTAP phosphorylation.

Conclusions:

  • MDV US3 directly phosphorylates WTAP, inhibiting its function in m6A modification.
  • This phosphorylation event disrupts cellular protein translation, contributing to the MDV life cycle.
  • The findings provide novel insights into the molecular pathogenesis of Marek's disease virus.
Keywords:
Marek's disease virusN6-methyladenosineU(S)3Wilms tumor 1-associated protein

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