E3 ubiquitin ligase Deltex facilitates the expansion of Wingless gradient and antagonizes Wingless signaling through a conserved mechanism of transcriptional effector Armadillo/β-catenin degradation

Elife. 2024 Jun 20:12:RP88466. doi: 10.7554/eLife.88466.

Abstract

The Wnt/Wg pathway controls myriads of biological phenomena throughout the development and adult life of all organisms across the phyla. Thus, an aberrant Wnt signaling is associated with a wide range of pathologies in humans. Tight regulation of Wnt/Wg signaling is required to maintain proper cellular homeostasis. Here, we report a novel role of E3 ubiquitin ligase Deltex in Wg signaling regulation. Drosophila dx genetically interacts with wg and its pathway components. Furthermore, Dx LOF results in a reduced spreading of Wg while its over-expression expands the diffusion gradient of the morphogen. We attribute this change in Wg gradient to the endocytosis of Wg through Dx which directly affects the short- and long-range Wg targets. We also demonstrate the role of Dx in regulating Wg effector Armadillo where Dx down-regulates Arm through proteasomal degradation. We also showed the conservation of Dx function in the mammalian system where DTX1 is shown to bind with β-catenin and facilitates its proteolytic degradation, spotlighting a novel step that potentially modulates Wnt/Wg signaling cascade.

Keywords: Armadillo/β-catenin; D. melanogaster; E3 ubiquitin ligase; Wnt/Wingless signaling; deltex; developmental biology; endocytosis; ubiquitination.

MeSH terms

  • Animals
  • Armadillo Domain Proteins* / genetics
  • Armadillo Domain Proteins* / metabolism
  • Drosophila / genetics
  • Drosophila / metabolism
  • Drosophila Proteins* / genetics
  • Drosophila Proteins* / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Humans
  • Proteolysis*
  • Signal Transduction
  • Transcription Factors
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitin-Protein Ligases* / metabolism
  • Wnt Signaling Pathway
  • Wnt1 Protein* / genetics
  • Wnt1 Protein* / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • ARM protein, Drosophila
  • Armadillo Domain Proteins
  • beta Catenin
  • Drosophila Proteins
  • Transcription Factors
  • Ubiquitin-Protein Ligases
  • wg protein, Drosophila
  • Wnt1 Protein
  • DX protein, Drosophila