title: Active Interaction Mapping Reveals the Hierarchical Organization of Autophagy.
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/.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kramer
authors.affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Farré
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Koyel
authors.initials: K
authors.lastname: Mitra
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Michael Ku
authors.initials: MK
authors.lastname: Yu
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Ono
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Demchak
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Licon
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Flagg
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94304, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Balakrishnan
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94304, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Cherry
authors.affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: ssubramani@ucsd.edu.
authors.forename: Suresh
authors.initials: S
authors.lastname: Subramani
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: tideker@ucsd.edu.
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
mesh_terms: D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins / Q000235:genetics / Q000378:metabolism; D030541:Databases, Genetic; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D053263:Gene Regulatory Networks; D023281:Genomics / Q000379:methods*; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008957:Models, Genetic; D010843:Pichia / Q000235:genetics / Q000378:metabolism; D060066:Protein Interaction Maps; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D049490:Systems Biology / Q000379:methods*; D018511:Systems Integration
chemical_list: D000071183:Autophagy-Related Proteins; C524222:DID4 protein, S cerevisiae; D056827:Endosomal Sorting Complexes Required for Transport; D020690:GTPase-Activating Proteins; C416529:GYP1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C485219:Ssd1 protein, S cerevisiae; C518958:Atg26 protein, S cerevisiae; D005964:Glucosyltransferases
keywords: active interaction mapping; autophagy; hierarchical modeling; human; systems biology; yeast