Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 22, Issue 5, Pages 673-686Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E10-08-0738
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Funding
- National Institute of Neurological Disorders and Stroke [P30 NS-047101]
- National Institute of Diabetes and Digestive and Kidney Diseases [DK-80506]
- Burroughs Wellcome Fund
- American Gastroenterology Association FDN
- National Institutes of Health [DK-I7780]
- Susan G. Komen postdoctoral fellowship [KG080079]
- UCSD
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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 G alpha-interacting, vesicle-associated protein (GIV, a.k.a. Girdin), a nonreceptor guanine nucleotide exchange factor for G alpha(i3), plays a key role in regulating autophagy and that dynamic interplay between G alpha(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 G alpha(i3) to LC3-positive membranes upon starvation, and promotes autophagy by inhibiting the G protein. Upon growth factor stimulation, GIV disrupts the G alpha(i3)-AGS3 complex, releases G alpha(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 G alpha(i3) activity by AGS3 and GIV maintains the delicate equilibrium between promotion and inhibition of autophagy.
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