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<p>Insulin/insulin-like growth factor signaling inhibits FOXO transcription factors to control development, homeostasis, and aging. Here, we use proximity labeling to identify proteins interacting with the <i>C. elegans</i> FOXO DAF-16. We show that in well-fed, unstressed animals harboring active insulin signaling, DAF-16 forms a complex with the PAR-1/MARK serine/threonine kinase, a key regulator of cell polarity. PAR-1 inhibits DAF-16 accumulation and promotes DAF-16 phosphorylation at S249, at a conserved motif that PAR-1/human MARK2 phosphorylates in vitro. DAF-2 insulin-like receptor signaling stimulates DAF-16 S249 phosphorylation, suggesting DAF-2 activates PAR-1. DAF-2 also promotes PAR-1 expression by inhibiting DAF-16. PAR-1 knockdown, or DAF-16 S249A, prolong lifespan, whereas phosphomimetic DAF-16 S249D suppresses the longevity of <i>daf-2</i> mutants. At low insulin signaling, DAF-16 proximity labeling highlights transcription factors, chromatin regulators, and DNA repair proteins. One interactor, the zinc finger/homeobox protein ZFH-2/ZFHX3, forms a complex with DAF-16 and prolongs lifespan. Our work provides entry points for hypothesis-driven studies of FOXO function and longevity.</p>

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Proximity labeling of DAF-16 FOXO highlights aging regulatory proteins

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月11日

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  • Murat Artan,
  • Hanna Schoen,
  • Mario de Bono

摘要

Insulin/insulin-like growth factor signaling inhibits FOXO transcription factors to control development, homeostasis, and aging. Here, we use proximity labeling to identify proteins interacting with the C. elegans FOXO DAF-16. We show that in well-fed, unstressed animals harboring active insulin signaling, DAF-16 forms a complex with the PAR-1/MARK serine/threonine kinase, a key regulator of cell polarity. PAR-1 inhibits DAF-16 accumulation and promotes DAF-16 phosphorylation at S249, at a conserved motif that PAR-1/human MARK2 phosphorylates in vitro. DAF-2 insulin-like receptor signaling stimulates DAF-16 S249 phosphorylation, suggesting DAF-2 activates PAR-1. DAF-2 also promotes PAR-1 expression by inhibiting DAF-16. PAR-1 knockdown, or DAF-16 S249A, prolong lifespan, whereas phosphomimetic DAF-16 S249D suppresses the longevity of daf-2 mutants. At low insulin signaling, DAF-16 proximity labeling highlights transcription factors, chromatin regulators, and DNA repair proteins. One interactor, the zinc finger/homeobox protein ZFH-2/ZFHX3, forms a complex with DAF-16 and prolongs lifespan. Our work provides entry points for hypothesis-driven studies of FOXO function and longevity.