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Manganese mediates antiviral effects by driving an ATM -TBK1 phosphorylation signaling pathway

Hongyan Sui1, Rosana Wiscovitch-Russo1, Silvia Cachaco1,2

  • 1Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory, Frederick, MD, United States.

Frontiers in Immunology
|December 5, 2025
PubMed

Insights

Manganese (Mn) activates the cytoplasmic Ataxia-telangiectasia mutated (ATM) kinase, leading to TBK1 phosphorylation. This pathway enhances antiviral cytokine production and inhibits HIV replication, suggesting Mn as a potential antiviral therapy.

Area of Science:

  • Cellular Biology
  • Immunology
  • Virology

Background:

  • Ataxia-telangiectasia mutated (ATM) is a nuclear kinase primarily known for its role in DNA damage repair.
  • Previous research indicated ATM's involvement in a manganese (Mn)-dependent TBK1 phosphorylation pathway, but the mechanism was unclear.

Purpose of the Study:

  • To elucidate the mechanism by which manganese (Mn) induces TBK1 phosphorylation via ATM.
  • To investigate the role of this pathway in innate immunity and viral replication, specifically HIV.

Main Methods:

  • Utilized multiple cell lines, primary human macrophages, and T cells.
  • Performed dose-response experiments with Mn and assessed TBK1 phosphorylation in the presence and absence of ATM.
  • Conducted immunoprecipitation assays to analyze ATM phosphorylation and TBK1-ATM complex dynamics.

Main Results:

  • Mn dose-dependently induced TBK1 phosphorylation in an ATM-dependent manner, primarily mediated by cytoplasmic ATM.
  • Mn promoted ATM phosphorylation at specific sites (Ser1891, Ser1981, Ser2996).
  • TBK1 dissociated from ATM upon phosphorylation, correlating with increased antiviral cytokine production and inhibited HIV replication.

Conclusions:

  • Identified a cytoplasmic ATM-TBK1 phosphorylation cycle crucial for regulating antiviral innate immunity.
  • Demonstrated that Mn inhibits HIV replication through this pathway.
  • Proposed Mn supplementation as a potential therapeutic strategy for viral infections like HIV.
Keywords:
ATMTBK1antiviral immunitymanganesephosphorylation

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