A GDI (AGS3) and a GEF (GIV) regulate autophagy by balancing G protein activity and growth factor signals.
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.
Mesh Terms:
Autophagy, Binding, Competitive, Carrier Proteins, Cell Membrane, GTP-Binding Protein alpha Subunits, Gi-Go, Guanine Nucleotide Dissociation Inhibitors, HeLa Cells, Humans, Insulin, Intercellular Signaling Peptides and Proteins, Microfilament Proteins, Microtubule-Associated Proteins, Phagosomes, Protein Binding, Protein Interaction Mapping, Protein Structure, Secondary, Protein Transport, Proto-Oncogene Proteins c-akt, Signal Transduction, TOR Serine-Threonine Kinases, Vesicular Transport Proteins
Autophagy, Binding, Competitive, Carrier Proteins, Cell Membrane, GTP-Binding Protein alpha Subunits, Gi-Go, Guanine Nucleotide Dissociation Inhibitors, HeLa Cells, Humans, Insulin, Intercellular Signaling Peptides and Proteins, Microfilament Proteins, Microtubule-Associated Proteins, Phagosomes, Protein Binding, Protein Interaction Mapping, Protein Structure, Secondary, Protein Transport, Proto-Oncogene Proteins c-akt, Signal Transduction, TOR Serine-Threonine Kinases, Vesicular Transport Proteins
Mol. Biol. Cell
Date: Mar. 01, 2011
PubMed ID: 21209316
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