Active Interaction Mapping Reveals the Hierarchical Organization of Autophagy

Mol Cell. 2017 Feb 16;65(4):761-774.e5. doi: 10.1016/j.molcel.2016.12.024. Epub 2017 Jan 26.


We have developed a general progressive procedure, Active Interaction Mapping, to guide assembly of the hierarchy of functions encoding any biological system. Using this process, we assemble an ontology of functions comprising autophagy, a central recycling process implicated in numerous diseases. A first-generation model, built from existing gene networks in Saccharomyces, captures most known autophagy components in broad relation to vesicle transport, cell cycle, and stress response. Systematic analysis identifies synthetic-lethal interactions as most informative for further experiments; consequently, we saturate the model with 156,364 such measurements across autophagy-activating conditions. These targeted interactions provide more information about autophagy than all previous datasets, producing a second-generation ontology of 220 functions. Approximately half are previously unknown; we confirm roles for Gyp1 at the phagophore-assembly site, Atg24 in cargo engulfment, Atg26 in cytoplasm-to-vacuole targeting, and Ssd1, Did4, and others in selective and non-selective autophagy. The procedure and autophagy hierarchy are at

Keywords: active interaction mapping; autophagy; hierarchical modeling; human; systems biology; yeast.

MeSH terms

  • Autophagy / genetics*
  • Autophagy-Related Proteins / genetics
  • Autophagy-Related Proteins / metabolism
  • Databases, Genetic
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism
  • Gene Expression Regulation, Fungal
  • Gene Regulatory Networks*
  • Genomics / methods*
  • Glucosyltransferases / genetics
  • Glucosyltransferases / metabolism
  • Humans
  • Models, Genetic
  • Pichia / genetics
  • Pichia / metabolism
  • Protein Interaction Maps
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Systems Biology / methods*
  • Systems Integration


  • Autophagy-Related Proteins
  • DID4 protein, S cerevisiae
  • Endosomal Sorting Complexes Required for Transport
  • GTPase-Activating Proteins
  • GYP1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Ssd1 protein, S cerevisiae
  • Atg26 protein, S cerevisiae
  • Glucosyltransferases