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

Active Interaction Mapping Reveals the Hierarchical Organization of Autophagy.

Author information

1
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
2
Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Genetics, Stanford University, Stanford, CA 94304, USA.
4
Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: ssubramani@ucsd.edu.
5
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: tideker@ucsd.edu.

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/.

KEYWORDS:

active interaction mapping; autophagy; hierarchical modeling; human; systems biology; yeast

PMID:
28132844
PMCID:
PMC5439305
DOI:
10.1016/j.molcel.2016.12.024
[Indexed for MEDLINE]
Free PMC Article

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