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The BPAN and intellectual disability disease proteins WDR45 and WDR45B modulate autophagosome-lysosome fusion

Cuicui Ji1, Yan G Zhao2

  • 1National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P.R. China.

Autophagy
|June 9, 2021
PubMed

Insights

WDR45 and WDR45B proteins are crucial for autophagosome-lysosome fusion in neural cells. Their dysfunction, linked to neurodegenerative diseases, disrupts cellular waste clearance pathways.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Neuroscience

Background:

  • WDR45 and WDR45B are WIPI family proteins, homologous to yeast Atg18, involved in cellular processes.
  • Mutations in WDR45 and WDR45B are associated with neurodegenerative disorders like beta-propeller protein-associated neurodegeneration (BPAN) and intellectual disability (ID).

Purpose of the Study:

  • To investigate the role of WDR45 and WDR45B in autophagosome-lysosome fusion in neural cells.
  • To elucidate the molecular mechanisms underlying WDR45 and WDR45B function in relation to neurological diseases.

Main Methods:

  • Investigated the interaction of WDR45 and WDR45B with the tether protein EPG5.
  • Analyzed autophagosome-lysosome fusion in Wdr45 Wdr45b-deficient cells.
  • Examined the effect of O-GlcNAcylation suppression on autophagy in deficient cells.

Main Results:

  • WDR45 and WDR45B are essential for autophagosome-lysosome fusion in neural cells.
  • WDR45 and WDR45B bind to EPG5, facilitating its localization to late endosomes/lysosomes.
  • Deficiency in WDR45 and WDR45B impairs the tether-SNARE fusion machinery.
  • Suppression of O-GlcNAcylation ameliorates the autophagy defect in Wdr45 Wdr45b-deficient cells.

Conclusions:

  • WDR45 and WDR45B play a critical role in autophagosome-lysosome fusion, a process vital for neural health.
  • Dysregulation of WDR45 and WDR45B function contributes to the pathogenesis of associated neurological disorders.
  • Targeting O-GlcNAcylation may offer therapeutic potential for WDR45/WDR45B-related diseases.
Keywords:
AutophagyBPANIDWDR45WDR45Bautophagosome maturation

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