title: A GDI (AGS3) and a GEF (GIV) regulate autophagy by balancing G protein activity and growth factor signals.
abstract: Autophagy is the major catabolic process responsible for the removal of aggregated proteins and damaged organelles. Autophagy is regulated by both G proteins and growth factors, but the underlying mechanism of how they are coordinated during initiation and reversal of autophagy is unknown. Using protein-protein interaction assays, G protein enzymology, and morphological analysis, we demonstrate here that Gα-interacting, vesicle-associated protein (GIV, a. k. a. Girdin), a nonreceptor guanine nucleotide exchange factor for Gα(i3), plays a key role in regulating autophagy and that dynamic interplay between Gα(i3), activator of G-protein signaling 3 (AGS3, its guanine nucleotide dissociation inhibitor), and GIV determines whether autophagy is promoted or inhibited. We found that AGS3 directly binds light chain 3 (LC3), recruits Gα(i3) to LC3-positive membranes upon starvation, and promotes autophagy by inhibiting the G protein. Upon growth factor stimulation, GIV disrupts the Gα(i3)-AGS3 complex, releases Gα(i3) from LC3-positive membranes, enhances anti-autophagic signaling pathways, and inhibits autophagy by activating the G protein. These results provide mechanistic insights into how reversible modulation of Gα(i3) activity by AGS3 and GIV maintains the delicate equilibrium between promotion and inhibition of autophagy.
authors.affiliation: Departments of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093 , USA. mgarciamarcos@ucsd.edu
authors.forename: Mikel
authors.initials: M
authors.lastname: Garcia-Marcos
authors.forename: Jason
authors.initials: J
authors.lastname: Ear
authors.forename: Marilyn G
authors.initials: MG
authors.lastname: Farquhar
authors.forename: Pradipta
authors.initials: P
authors.lastname: Ghosh
mesh_terms: D001343:Autophagy / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D020730:Guanine Nucleotide Dissociation Inhibitors; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D017433:Protein Structure, Secondary; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: C502451:CCDC88A protein, human; D002352:Carrier Proteins; C525615:GPSM1 protein, human; D020730:Guanine Nucleotide Dissociation Inhibitors; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; C477012:MAP1LC3A protein, human; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D033921:Vesicular Transport Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C498819:GNAI3 protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go