Noncanonical roles of ATG5 and membrane atg8ylation in retromer assembly and function

Elife. 2025 Jan 7:13:RP100928. doi: 10.7554/eLife.100928.

Abstract

ATG5 is one of the core autophagy proteins with additional functions such as noncanonical membrane atg8ylation, which among a growing number of biological outputs includes control of tuberculosis in animal models. Here, we show that ATG5 associates with retromer's core components VPS26, VPS29, and VPS35 and modulates retromer function. Knockout of ATG5 blocked trafficking of a key glucose transporter sorted by the retromer, GLUT1, to the plasma membrane. Knockouts of other genes essential for membrane atg8ylation, of which ATG5 is a component, affected GLUT1 sorting, indicating that membrane atg8ylation as a process affects retromer function and endosomal sorting. The contribution of membrane atg8ylation to retromer function in GLUT1 sorting was independent of canonical autophagy. These findings expand the scope of membrane atg8ylation to specific sorting processes in the cell dependent on the retromer and its known interactors.

Keywords: active tuberculosis; atg8ylation; autophagy; cell biology; glucose transport; human; latent tuberculosis; membrane transport; mouse.

MeSH terms

  • Autophagy
  • Autophagy-Related Protein 5* / genetics
  • Autophagy-Related Protein 5* / metabolism
  • Autophagy-Related Protein 8 Family / genetics
  • Autophagy-Related Protein 8 Family / metabolism
  • Cell Membrane / metabolism
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism
  • Humans
  • Protein Transport*
  • Vesicular Transport Proteins* / genetics
  • Vesicular Transport Proteins* / metabolism

Substances

  • Vesicular Transport Proteins
  • Autophagy-Related Protein 5
  • Glucose Transporter Type 1
  • Autophagy-Related Protein 8 Family
  • VPS29 protein, human
  • VPS26A protein, human
  • VPS35 protein, human
  • SLC2A1 protein, human