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A GDI (AGS3) and a GEF (GIV) regulate autophagy by balancing G protein activity and growth factor signals.

Garcia-Marcos M, Ear J, Farquhar MG, Ghosh P - Mol. Biol. Cell (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093 , USA. mgarciamarcos@ucsd.edu

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.

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GIV-CTs and AGS3 compete for binding to Gαi3. (A) GIV’s GEF motif and RGS14’s GoLoco motif have overlapping binding sites on Gαi subunits. Left, a homology model of GIV’s GEF motif (shown in red) bound to GDP–Gαi3 was generated as described previously (Garcia-Marcos et al., 2009) using the structure of the synthetic peptide KB-752 bound to Gαi1 (PDB:1Y3A) as a template. Right, structural model of RGS14’s GoLoco motif (shown in pink) bound to Gαi1 was generated using the coordinates of the published crystal structure (Kimple et al., 2002). In both panels, the “ras-like” domain of Gαi3 is shown in blue, the “all-helical” domain in yellow, and the three “switch” regions (SI, SII, and SIII) in green. GIV’s GEF and RGS14’s GoLoco motifs dock onto the same cleft formed between the switch II and the α3 helix of the G protein. (B) GIV-CTs displaced Gαi3 from Gαi3–AGS3 complexes. Purified His-Gαi3:GST-AGS3 complexes were incubated with increasing amounts of His-GIV-CT (0, 0.5, 1, and 2 μM), and subsequently the GST–AGS3-bound complexes were immobilized on glutathione-agarose beads followed by centrifugation. GST–AGS3-bound proteins in the pellet were eluted with SDS–PAGE sample buffer. Bound proteins (left panel) and unbound proteins (right panel) were analyzed for His (His-Gαi3, His-GIV-CTs) and AGS3 (GST-AGS3) by immunoblotting (IB). His-Gαi3 was simultaneously depleted from the GST–AGS3-bound fraction (left panel) and enriched in the supernatant (right panel). Note that under these experimental conditions binding of His-Gαi3:GST-AGS3 complexes to glutathione-agarose beads is incomplete, as evidenced by its presence in the supernatant even in the absence of His-GIV-CTs (right panel, first lane). (C) GIV-CTs displaces AGS3 from Gαi3–AGS3 complexes. GST–Gαi3 was incubated with His-AGS3 (0.1 μg) overnight at 4°C. The unbound His-AGS3 was washed, and the GST–Gαi3-bound complexes were then incubated with increasing amounts His-GIV-CTs (0, 1.2, 1.8 μM). GST–Gαi3-bound proteins were eluted with SDS–PAGE sample buffer and analyzed for His (His-GIV-CTs, His-AGS3) and Gαi3 (GST-Gαi3) by IB. Increased His-GIV-CTs binding to GST-Gαi3 are accompanied by decreased His-AGS3 binding. (D) AGS3 sequesters Gαi3 from Gαi3–GIV complexes. Purified His-Gαi3:His-GIV-CTs complexes were incubated with increasing amounts of GST–AGS3 (0, 0.05, 0.1, and 0.5 μM), and the resulting GST–AGS3-bound complexes were immobilized on glutathione-agarose beads followed by centrifugation. GST–AGS3-bound proteins in the pellet were eluted with SDS–PAGE sample buffer. Bound proteins (left panel) and unbound proteins (right panel) were analyzed for His (His-Gαi3, His-GIV-CTs) and AGS3 (GST-AGS3) by IB. His-Gαi3 was depleted from the supernatant (right panel) and concomitantly enriched in the GST–AGS3-bound complexes with increasing His-GIV-CTs concentration. (E) AGS3 displaces GIV from Gαi3–GIV complexes. GST–Gα i3 was incubated with His-GIV-CTs (6 μg) overnight at 4°C. The unbound His-GIV-CTs were washed, and the GST–Gαi3-bound complexes were incubated with increasing amounts His-AGS3 (0, 0.02, and 0.04 μM). GST–Gαi3-bound proteins were eluted with SDS–PAGE sample buffer and analyzed for His (His-GIV-CTs, His-AGS3) and Gαi3 (GST–Gαi3) by IB. Increased binding of His-AGS3 to GST–Gαi3 is accompanied by decreased His-GIV-CTs binding. AGS3 displaced GIV from Gαi3 at lower concentrations (D, E) than those required for GIV to displace AGS3 (B, C), which is consistent with the fact that AGS3 has four Gαi binding sites with Kd ≈ 30–100 nM (Adhikari and Sprang, 2003), and GIV has only one binding site with Kd ≈ 300 nM (unpublished data).
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Figure 3: GIV-CTs and AGS3 compete for binding to Gαi3. (A) GIV’s GEF motif and RGS14’s GoLoco motif have overlapping binding sites on Gαi subunits. Left, a homology model of GIV’s GEF motif (shown in red) bound to GDP–Gαi3 was generated as described previously (Garcia-Marcos et al., 2009) using the structure of the synthetic peptide KB-752 bound to Gαi1 (PDB:1Y3A) as a template. Right, structural model of RGS14’s GoLoco motif (shown in pink) bound to Gαi1 was generated using the coordinates of the published crystal structure (Kimple et al., 2002). In both panels, the “ras-like” domain of Gαi3 is shown in blue, the “all-helical” domain in yellow, and the three “switch” regions (SI, SII, and SIII) in green. GIV’s GEF and RGS14’s GoLoco motifs dock onto the same cleft formed between the switch II and the α3 helix of the G protein. (B) GIV-CTs displaced Gαi3 from Gαi3–AGS3 complexes. Purified His-Gαi3:GST-AGS3 complexes were incubated with increasing amounts of His-GIV-CT (0, 0.5, 1, and 2 μM), and subsequently the GST–AGS3-bound complexes were immobilized on glutathione-agarose beads followed by centrifugation. GST–AGS3-bound proteins in the pellet were eluted with SDS–PAGE sample buffer. Bound proteins (left panel) and unbound proteins (right panel) were analyzed for His (His-Gαi3, His-GIV-CTs) and AGS3 (GST-AGS3) by immunoblotting (IB). His-Gαi3 was simultaneously depleted from the GST–AGS3-bound fraction (left panel) and enriched in the supernatant (right panel). Note that under these experimental conditions binding of His-Gαi3:GST-AGS3 complexes to glutathione-agarose beads is incomplete, as evidenced by its presence in the supernatant even in the absence of His-GIV-CTs (right panel, first lane). (C) GIV-CTs displaces AGS3 from Gαi3–AGS3 complexes. GST–Gαi3 was incubated with His-AGS3 (0.1 μg) overnight at 4°C. The unbound His-AGS3 was washed, and the GST–Gαi3-bound complexes were then incubated with increasing amounts His-GIV-CTs (0, 1.2, 1.8 μM). GST–Gαi3-bound proteins were eluted with SDS–PAGE sample buffer and analyzed for His (His-GIV-CTs, His-AGS3) and Gαi3 (GST-Gαi3) by IB. Increased His-GIV-CTs binding to GST-Gαi3 are accompanied by decreased His-AGS3 binding. (D) AGS3 sequesters Gαi3 from Gαi3–GIV complexes. Purified His-Gαi3:His-GIV-CTs complexes were incubated with increasing amounts of GST–AGS3 (0, 0.05, 0.1, and 0.5 μM), and the resulting GST–AGS3-bound complexes were immobilized on glutathione-agarose beads followed by centrifugation. GST–AGS3-bound proteins in the pellet were eluted with SDS–PAGE sample buffer. Bound proteins (left panel) and unbound proteins (right panel) were analyzed for His (His-Gαi3, His-GIV-CTs) and AGS3 (GST-AGS3) by IB. His-Gαi3 was depleted from the supernatant (right panel) and concomitantly enriched in the GST–AGS3-bound complexes with increasing His-GIV-CTs concentration. (E) AGS3 displaces GIV from Gαi3–GIV complexes. GST–Gα i3 was incubated with His-GIV-CTs (6 μg) overnight at 4°C. The unbound His-GIV-CTs were washed, and the GST–Gαi3-bound complexes were incubated with increasing amounts His-AGS3 (0, 0.02, and 0.04 μM). GST–Gαi3-bound proteins were eluted with SDS–PAGE sample buffer and analyzed for His (His-GIV-CTs, His-AGS3) and Gαi3 (GST–Gαi3) by IB. Increased binding of His-AGS3 to GST–Gαi3 is accompanied by decreased His-GIV-CTs binding. AGS3 displaced GIV from Gαi3 at lower concentrations (D, E) than those required for GIV to displace AGS3 (B, C), which is consistent with the fact that AGS3 has four Gαi binding sites with Kd ≈ 30–100 nM (Adhikari and Sprang, 2003), and GIV has only one binding site with Kd ≈ 300 nM (unpublished data).

Mentions: To investigate whether reversible modulation of Gαi3 activity by GIV and AGS3 depends on their intermolecular interactions, we took advantage of the available structural information. We compared the homology model (Figure 3A) of GIV’s GEF motif bound to Gαi3, which we previously validated (Garcia-Marcos et al., 2009), with the crystal structure of Gαi1 bound to the Gαi/o-Loco (GoLoco) motif of RGS14, which is homologous to the GoLoco motifs in AGS3 that are responsible for its GDI activity (Kimple et al., 2002). Comparative analysis revealed that GIV’s GEF and RGS14’s GoLoco motifs have overlapping binding sites on Gαi in that both dock onto the cleft formed between the switch II and the α3 helix of the G protein (Figure 3A), suggesting that AGS3 and GIV might compete for binding to Gαi3. To test this possibility, we first determined whether increasing concentrations of His-GIV-CTs are capable of displacing His-Gαi3 from His-Gαi3:GST-AGS3 complexes and found that this is the case: With increasing concentrations of His-GIV-CTs, the amount of His-Gαi3 bound to immobilized GST-AGS3 decreased with a concomitant release of His-Gαi3 into the supernatant (Figure 3B), suggesting that GIV competes with AGS3 for binding to Gαi3 and can displace AGS3 from Gαi3. We confirmed this finding using a complementary approach in which His-AGS3 was prebound to immobilized GST-Gαi3 and subsequently incubated with increasing amounts of His-GIV-CTs. GIV displaced AGS3 from Gαi3, as evident from the decreased amount of His-AGS3 bound to immobilized GST-Gαi3 and the concomitant increase in His-GIV-CTs binding (Figure 3C). Finally, using GST-Gαi3 and Cos7 cell lysate or rat brain as the source of full-length AGS3, we confirmed that His-GIV-CTs is also capable of competing with and displacing full-length AGS3 from Gαi3 (unpublished data).


A GDI (AGS3) and a GEF (GIV) regulate autophagy by balancing G protein activity and growth factor signals.

Garcia-Marcos M, Ear J, Farquhar MG, Ghosh P - Mol. Biol. Cell (2011)

GIV-CTs and AGS3 compete for binding to Gαi3. (A) GIV’s GEF motif and RGS14’s GoLoco motif have overlapping binding sites on Gαi subunits. Left, a homology model of GIV’s GEF motif (shown in red) bound to GDP–Gαi3 was generated as described previously (Garcia-Marcos et al., 2009) using the structure of the synthetic peptide KB-752 bound to Gαi1 (PDB:1Y3A) as a template. Right, structural model of RGS14’s GoLoco motif (shown in pink) bound to Gαi1 was generated using the coordinates of the published crystal structure (Kimple et al., 2002). In both panels, the “ras-like” domain of Gαi3 is shown in blue, the “all-helical” domain in yellow, and the three “switch” regions (SI, SII, and SIII) in green. GIV’s GEF and RGS14’s GoLoco motifs dock onto the same cleft formed between the switch II and the α3 helix of the G protein. (B) GIV-CTs displaced Gαi3 from Gαi3–AGS3 complexes. Purified His-Gαi3:GST-AGS3 complexes were incubated with increasing amounts of His-GIV-CT (0, 0.5, 1, and 2 μM), and subsequently the GST–AGS3-bound complexes were immobilized on glutathione-agarose beads followed by centrifugation. GST–AGS3-bound proteins in the pellet were eluted with SDS–PAGE sample buffer. Bound proteins (left panel) and unbound proteins (right panel) were analyzed for His (His-Gαi3, His-GIV-CTs) and AGS3 (GST-AGS3) by immunoblotting (IB). His-Gαi3 was simultaneously depleted from the GST–AGS3-bound fraction (left panel) and enriched in the supernatant (right panel). Note that under these experimental conditions binding of His-Gαi3:GST-AGS3 complexes to glutathione-agarose beads is incomplete, as evidenced by its presence in the supernatant even in the absence of His-GIV-CTs (right panel, first lane). (C) GIV-CTs displaces AGS3 from Gαi3–AGS3 complexes. GST–Gαi3 was incubated with His-AGS3 (0.1 μg) overnight at 4°C. The unbound His-AGS3 was washed, and the GST–Gαi3-bound complexes were then incubated with increasing amounts His-GIV-CTs (0, 1.2, 1.8 μM). GST–Gαi3-bound proteins were eluted with SDS–PAGE sample buffer and analyzed for His (His-GIV-CTs, His-AGS3) and Gαi3 (GST-Gαi3) by IB. Increased His-GIV-CTs binding to GST-Gαi3 are accompanied by decreased His-AGS3 binding. (D) AGS3 sequesters Gαi3 from Gαi3–GIV complexes. Purified His-Gαi3:His-GIV-CTs complexes were incubated with increasing amounts of GST–AGS3 (0, 0.05, 0.1, and 0.5 μM), and the resulting GST–AGS3-bound complexes were immobilized on glutathione-agarose beads followed by centrifugation. GST–AGS3-bound proteins in the pellet were eluted with SDS–PAGE sample buffer. Bound proteins (left panel) and unbound proteins (right panel) were analyzed for His (His-Gαi3, His-GIV-CTs) and AGS3 (GST-AGS3) by IB. His-Gαi3 was depleted from the supernatant (right panel) and concomitantly enriched in the GST–AGS3-bound complexes with increasing His-GIV-CTs concentration. (E) AGS3 displaces GIV from Gαi3–GIV complexes. GST–Gα i3 was incubated with His-GIV-CTs (6 μg) overnight at 4°C. The unbound His-GIV-CTs were washed, and the GST–Gαi3-bound complexes were incubated with increasing amounts His-AGS3 (0, 0.02, and 0.04 μM). GST–Gαi3-bound proteins were eluted with SDS–PAGE sample buffer and analyzed for His (His-GIV-CTs, His-AGS3) and Gαi3 (GST–Gαi3) by IB. Increased binding of His-AGS3 to GST–Gαi3 is accompanied by decreased His-GIV-CTs binding. AGS3 displaced GIV from Gαi3 at lower concentrations (D, E) than those required for GIV to displace AGS3 (B, C), which is consistent with the fact that AGS3 has four Gαi binding sites with Kd ≈ 30–100 nM (Adhikari and Sprang, 2003), and GIV has only one binding site with Kd ≈ 300 nM (unpublished data).
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Figure 3: GIV-CTs and AGS3 compete for binding to Gαi3. (A) GIV’s GEF motif and RGS14’s GoLoco motif have overlapping binding sites on Gαi subunits. Left, a homology model of GIV’s GEF motif (shown in red) bound to GDP–Gαi3 was generated as described previously (Garcia-Marcos et al., 2009) using the structure of the synthetic peptide KB-752 bound to Gαi1 (PDB:1Y3A) as a template. Right, structural model of RGS14’s GoLoco motif (shown in pink) bound to Gαi1 was generated using the coordinates of the published crystal structure (Kimple et al., 2002). In both panels, the “ras-like” domain of Gαi3 is shown in blue, the “all-helical” domain in yellow, and the three “switch” regions (SI, SII, and SIII) in green. GIV’s GEF and RGS14’s GoLoco motifs dock onto the same cleft formed between the switch II and the α3 helix of the G protein. (B) GIV-CTs displaced Gαi3 from Gαi3–AGS3 complexes. Purified His-Gαi3:GST-AGS3 complexes were incubated with increasing amounts of His-GIV-CT (0, 0.5, 1, and 2 μM), and subsequently the GST–AGS3-bound complexes were immobilized on glutathione-agarose beads followed by centrifugation. GST–AGS3-bound proteins in the pellet were eluted with SDS–PAGE sample buffer. Bound proteins (left panel) and unbound proteins (right panel) were analyzed for His (His-Gαi3, His-GIV-CTs) and AGS3 (GST-AGS3) by immunoblotting (IB). His-Gαi3 was simultaneously depleted from the GST–AGS3-bound fraction (left panel) and enriched in the supernatant (right panel). Note that under these experimental conditions binding of His-Gαi3:GST-AGS3 complexes to glutathione-agarose beads is incomplete, as evidenced by its presence in the supernatant even in the absence of His-GIV-CTs (right panel, first lane). (C) GIV-CTs displaces AGS3 from Gαi3–AGS3 complexes. GST–Gαi3 was incubated with His-AGS3 (0.1 μg) overnight at 4°C. The unbound His-AGS3 was washed, and the GST–Gαi3-bound complexes were then incubated with increasing amounts His-GIV-CTs (0, 1.2, 1.8 μM). GST–Gαi3-bound proteins were eluted with SDS–PAGE sample buffer and analyzed for His (His-GIV-CTs, His-AGS3) and Gαi3 (GST-Gαi3) by IB. Increased His-GIV-CTs binding to GST-Gαi3 are accompanied by decreased His-AGS3 binding. (D) AGS3 sequesters Gαi3 from Gαi3–GIV complexes. Purified His-Gαi3:His-GIV-CTs complexes were incubated with increasing amounts of GST–AGS3 (0, 0.05, 0.1, and 0.5 μM), and the resulting GST–AGS3-bound complexes were immobilized on glutathione-agarose beads followed by centrifugation. GST–AGS3-bound proteins in the pellet were eluted with SDS–PAGE sample buffer. Bound proteins (left panel) and unbound proteins (right panel) were analyzed for His (His-Gαi3, His-GIV-CTs) and AGS3 (GST-AGS3) by IB. His-Gαi3 was depleted from the supernatant (right panel) and concomitantly enriched in the GST–AGS3-bound complexes with increasing His-GIV-CTs concentration. (E) AGS3 displaces GIV from Gαi3–GIV complexes. GST–Gα i3 was incubated with His-GIV-CTs (6 μg) overnight at 4°C. The unbound His-GIV-CTs were washed, and the GST–Gαi3-bound complexes were incubated with increasing amounts His-AGS3 (0, 0.02, and 0.04 μM). GST–Gαi3-bound proteins were eluted with SDS–PAGE sample buffer and analyzed for His (His-GIV-CTs, His-AGS3) and Gαi3 (GST–Gαi3) by IB. Increased binding of His-AGS3 to GST–Gαi3 is accompanied by decreased His-GIV-CTs binding. AGS3 displaced GIV from Gαi3 at lower concentrations (D, E) than those required for GIV to displace AGS3 (B, C), which is consistent with the fact that AGS3 has four Gαi binding sites with Kd ≈ 30–100 nM (Adhikari and Sprang, 2003), and GIV has only one binding site with Kd ≈ 300 nM (unpublished data).
Mentions: To investigate whether reversible modulation of Gαi3 activity by GIV and AGS3 depends on their intermolecular interactions, we took advantage of the available structural information. We compared the homology model (Figure 3A) of GIV’s GEF motif bound to Gαi3, which we previously validated (Garcia-Marcos et al., 2009), with the crystal structure of Gαi1 bound to the Gαi/o-Loco (GoLoco) motif of RGS14, which is homologous to the GoLoco motifs in AGS3 that are responsible for its GDI activity (Kimple et al., 2002). Comparative analysis revealed that GIV’s GEF and RGS14’s GoLoco motifs have overlapping binding sites on Gαi in that both dock onto the cleft formed between the switch II and the α3 helix of the G protein (Figure 3A), suggesting that AGS3 and GIV might compete for binding to Gαi3. To test this possibility, we first determined whether increasing concentrations of His-GIV-CTs are capable of displacing His-Gαi3 from His-Gαi3:GST-AGS3 complexes and found that this is the case: With increasing concentrations of His-GIV-CTs, the amount of His-Gαi3 bound to immobilized GST-AGS3 decreased with a concomitant release of His-Gαi3 into the supernatant (Figure 3B), suggesting that GIV competes with AGS3 for binding to Gαi3 and can displace AGS3 from Gαi3. We confirmed this finding using a complementary approach in which His-AGS3 was prebound to immobilized GST-Gαi3 and subsequently incubated with increasing amounts of His-GIV-CTs. GIV displaced AGS3 from Gαi3, as evident from the decreased amount of His-AGS3 bound to immobilized GST-Gαi3 and the concomitant increase in His-GIV-CTs binding (Figure 3C). Finally, using GST-Gαi3 and Cos7 cell lysate or rat brain as the source of full-length AGS3, we confirmed that His-GIV-CTs is also capable of competing with and displacing full-length AGS3 from Gαi3 (unpublished data).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093 , USA. mgarciamarcos@ucsd.edu

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.

Show MeSH
Related in: MedlinePlus