Affiliation:
1. Departments of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093
2. Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093
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 Gαi3, plays a key role in regulating autophagy and that dynamic interplay between Gαi3, 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 Gαi3 to LC3-positive membranes upon starvation, and promotes autophagy by inhibiting the G protein. Upon growth factor stimulation, GIV disrupts the Gαi3–AGS3 complex, releases Gαi3 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 Gαi3 activity by AGS3 and GIV maintains the delicate equilibrium between promotion and inhibition of autophagy.
Publisher
American Society for Cell Biology (ASCB)
Subject
Cell Biology,Molecular Biology
Cited by
98 articles.
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