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DNA-PK-mediated phosphorylation of STAT6 establishes a non-canonical type 2 immunity axis to prevent macrophage

Zhao Zhou1, Xinmeng Li1, Yushuang Wang1

  • 1State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China.

Nature Communications
|February 24, 2026
PubMed

Insights

DNA-PK phosphorylates STAT6 to prevent macrophage senescence and inflammaging, a key factor in aging. This pathway is crucial for DNA repair and offers a therapeutic target for healthy aging.

Area of Science:

  • Immunology
  • Cellular Biology
  • Aging Research

Background:

  • Macrophage senescence contributes to inflammaging, a chronic, age-related inflammatory condition.
  • Mechanisms protecting against inflammaging are not well understood.
  • Identifying these protective pathways is critical for understanding and combating age-related diseases.

Purpose of the Study:

  • To identify key molecular mechanisms that prevent macrophage senescence.
  • To investigate the role of STAT6 post-translational modification in regulating macrophage senescence.
  • To explore the therapeutic potential of targeting the identified pathway for healthy aging.

Main Methods:

  • Investigated DNA-PK-mediated phosphorylation of STAT6 at serine 807 (Ser807) in macrophages.
  • Utilized phosphor-null (STAT6(S807A)) and phosphomimetic (STAT6(S807E)) STAT6 mutants in murine models.
  • Analyzed DNA repair gene activation, STAT6 ubiquitination, and senescence markers.
  • Assessed the impact of STAT6 phosphorylation on aging phenotypes in vivo.
  • Examined human STAT6 phosphorylation in lung tissue from patients with chronic obstructive pulmonary disease (COPD).

Main Results:

  • DNA-PK-mediated phosphorylation of STAT6 at Ser807 prevents its degradation and promotes DNA repair gene activation.
  • Macrophages lacking Ser807 phosphorylation exhibit DNA repair defects, leading to senescence and inflammaging.
  • In vivo, STAT6(S807A) accelerated aging phenotypes, while STAT6(S807E) expression rescued these effects.
  • Reduced STAT6 phosphorylation at the homologous Ser817 residue was observed in human COPD lungs, correlating with DNA damage and senescence.

Conclusions:

  • The DNA-PK-STAT6 axis is a critical regulator preventing macrophage senescence through enhanced DNA repair.
  • This pathway represents a novel mechanism in non-canonical type 2 immunity and a potential therapeutic target for promoting healthy aging.
  • Dysregulation of STAT6 phosphorylation is implicated in age-related diseases like COPD.

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