Title: Active Interaction Mapping Reveals the Hierarchical Organization of Autophagy.
Authors: Kramer, Michael H; Farré, Jean-Claude; Mitra, Koyel; Yu, Michael Ku; Ono, Keiichiro; Demchak, Barry; Licon, Katherine; Flagg, Mitchell; Balakrishnan, Rama; Cherry, J Michael; Subramani, Suresh; Ideker, Trey
Published In Mol Cell, (2017 Feb 16)
Abstract: 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 http://atgo.ucsd.edu/.
PubMed ID: 28132844
MeSH Terms: Autophagy-Related Proteins/genetics; Autophagy-Related Proteins/metabolism; Autophagy/genetics*; 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 Proteins/genetics*; Saccharomyces cerevisiae Proteins/metabolism; Saccharomyces cerevisiae/genetics*; Saccharomyces cerevisiae/metabolism; Systems Biology/methods*; Systems Integration