HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels

Nat Commun. 2016 Dec 22:7:13889. doi: 10.1038/ncomms13889.


A fundamental question is how autophagosome formation is regulated. Here we show that the PX domain protein HS1BP3 is a negative regulator of autophagosome formation. HS1BP3 depletion increased the formation of LC3-positive autophagosomes and degradation of cargo both in human cell culture and in zebrafish. HS1BP3 is localized to ATG16L1- and ATG9-positive autophagosome precursors and we show that HS1BP3 binds phosphatidic acid (PA) through its PX domain. Furthermore, we find the total PA content of cells to be significantly upregulated in the absence of HS1BP3, as a result of increased activity of the PA-producing enzyme phospholipase D (PLD) and increased localization of PLD1 to ATG16L1-positive membranes. We propose that HS1BP3 regulates autophagy by modulating the PA content of the ATG16L1-positive autophagosome precursor membranes through PLD1 activity and localization. Our findings provide key insights into how autophagosome formation is regulated by a novel negative-feedback mechanism on membrane lipids.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Autophagosomes / metabolism
  • Autophagy / physiology*
  • Autophagy-Related Proteins / metabolism
  • Cell Line
  • Cortactin / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Membrane Lipids / metabolism
  • Models, Biological
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • Phosphatidic Acids / metabolism*
  • Phospholipase D / metabolism
  • Protein Domains
  • Zebrafish
  • Zebrafish Proteins / metabolism


  • ATG16L1 protein, human
  • Autophagy-Related Proteins
  • CTTN protein, human
  • Cortactin
  • HS1BP3 protein, human
  • Membrane Lipids
  • Nerve Tissue Proteins
  • Phosphatidic Acids
  • Zebrafish Proteins
  • Phospholipase D
  • phospholipase D1

Associated data

  • Dryad/10.5061/dryad.gq3fk