title: Evolutionary trends and functional anatomy of the human expanded autophagy network.
abstract: All eukaryotic cells utilize autophagy for protein and organelle turnover, thus assuring subcellular quality control, homeostasis, and survival. In order to address recent advances in identification of human autophagy associated genes, and to describe autophagy on a system-wide level, we established an autophagy-centered gene interaction network by merging various primary data sets and by retrieving respective interaction data. The resulting network ('AXAN') was analyzed with respect to subnetworks, e.g. the prime gene subnetwork (including the core machinery, signaling pathways and autophagy receptors) and the transcription subnetwork. To describe aspects of evolution within this network, we assessed the presence of protein orthologs across 99 eukaryotic model organisms. We visualized evolutionary trends for prime gene categories and evolutionary tracks for selected AXAN genes. This analysis confirms the eukaryotic origin of autophagy core genes while it points to a diverse evolutionary history of autophagy receptors. Next, we used module identification to describe the functional anatomy of the network at the level of pathway modules. In addition to obvious pathways (e.g., lysosomal degradation, insulin signaling) our data unveil the existence of context-related modules such as Rho GTPase signaling. Last, we used a tripartite, image-based RNAi - screen to test candidate genes predicted to play a role in regulation of autophagy. We verified the Rho GTPase, CDC42, as a novel regulator of autophagy-related signaling. This study emphasizes the applicability of system-wide approaches to gain novel insights into a complex biological process and to describe the human autophagy pathway at a hitherto unprecedented level of detail.
authors.affiliation: a Section of Molecular Biology; University of California San Diego ; La Jolla , CA USA.|b The San Diego Center for Systems Biology ; La Jolla , CA USA.|c Stem Cell Pathologies Group/Life&Brain GmbH; University Clinic Bonn ; Bonn , Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Till
authors.affiliation: b The San Diego Center for Systems Biology ; La Jolla , CA USA.|d Departments of Medicine and Bioengineering ; University of California San Diego ; La Jolla , CA USA.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Saito
authors.affiliation: b The San Diego Center for Systems Biology ; La Jolla , CA USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Merkurjev
authors.affiliation: a Section of Molecular Biology; University of California San Diego ; La Jolla , CA USA.|b The San Diego Center for Systems Biology ; La Jolla , CA USA.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: e Division of Infectious Diseases ; Department of Medicine University of California San Diego ; La Jolla , CA USA.
authors.forename: Gulam Hussain
authors.initials: GH
authors.lastname: Syed
authors.affiliation: b The San Diego Center for Systems Biology ; La Jolla , CA USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Kolnik
authors.affiliation: e Division of Infectious Diseases ; Department of Medicine University of California San Diego ; La Jolla , CA USA.
authors.forename: Aleem
authors.initials: A
authors.lastname: Siddiqui
authors.affiliation: c Stem Cell Pathologies Group/Life&Brain GmbH; University Clinic Bonn ; Bonn , Germany.|f Clinical Cooperation Unit Neurooncology; MediClin Robert Janker Klinik ; Bonn , Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Glas
authors.affiliation: c Stem Cell Pathologies Group/Life&Brain GmbH; University Clinic Bonn ; Bonn , Germany.|f Clinical Cooperation Unit Neurooncology; MediClin Robert Janker Klinik ; Bonn , Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Scheffler
authors.affiliation: b The San Diego Center for Systems Biology ; La Jolla , CA USA.|d Departments of Medicine and Bioengineering ; University of California San Diego ; La Jolla , CA USA.
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
authors.affiliation: a Section of Molecular Biology; University of California San Diego ; La Jolla , CA USA.|b The San Diego Center for Systems Biology ; La Jolla , CA USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Subramani
mesh_terms: D001343:Autophagy / Q000235:genetics*; D005075:Biological Evolution; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D006801:Humans; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: D020764:cdc42 GTP-Binding Protein
keywords: CDC42; Cytoscape; autophagy; evolution; network biology; systems biology