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A new HECT ubiquitin ligase regulating chemotaxis and development in Dictyostelium discoideum

Barbara Pergolizzi1, Enrico Bracco2, Salvatore Bozzaro3

  • 1Department of Clinical and Biological Sciences, University of Torino, AOU S. Luigi, Orbassano (TO) 10043, Italy.

Journal of Cell Science
|January 5, 2017
PubMed

Insights

A novel HECT ubiquitin ligase regulates Dictyostelium development and chemotaxis by modulating cyclic AMP (cAMP) signaling. This discovery offers new insights into G-protein-coupled receptor (GPCR) pathways and cell communication.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Developmental Biology

Background:

  • Cyclic AMP (cAMP) binding to G-protein-coupled receptors (GPCRs) is crucial for Dictyostelium chemotaxis and development.
  • The RasC-TORC2-PKB (also known as AKT) module, activated by cAMP, regulates cell polarization and adenylyl cyclase A (ACA) stimulation.
  • Mutants lacking the TORC2 Pia subunit (Rictor) exhibit defects in chemotaxis and development.

Purpose of the Study:

  • To identify genetic suppressors of the Pia mutant's chemotaxis and development defects.
  • To elucidate the molecular mechanisms underlying cAMP-mediated signaling and cell behavior regulation in Dictyostelium.

Main Methods:

  • Near-saturation mutagenesis of a Pia mutant using random gene disruption.
  • Selection and characterization of spontaneous suppressor mutants.
  • Gene tagging, knockout studies (adenylylcyclase B - ACB), and functional analysis of a novel HECT ubiquitin ligase.

Main Results:

  • Two suppressor mutants restored chemotaxis and development, rescuing PKB phosphorylation and cell polarization.
  • Suppression bypassed Pia-dependent ACA stimulation, revealing a role for adenylylcyclase B (ACB) in cAMP-dependent gene expression.
  • The suppressor gene encodes a novel HECT ubiquitin ligase (homologous to mammalian HERC1) with a pleckstrin homology domain, essential for restoring the parental phenotype.

Conclusions:

  • A newly identified HECT ubiquitin ligase regulates cellular sensitivity to cAMP signaling and TORC2-dependent PKB phosphorylation.
  • This ligase plays a critical role in restoring chemotaxis and development in Dictyostelium lacking the TORC2 Pia subunit.
  • The findings uncover a novel component in the GPCR-mediated cAMP signaling pathway impacting cell behavior and development.
Keywords:
DictyosteliumHECT ubiquitin ligaseHERC1PiaRictorTORC2cAMP signalling

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