RalA-Exocyst Interaction Mediates GTP-dependent Exocytosis
Open accessAbstract
Many secretory cells utilize a GTP-dependent pathway, in addition to the well characterized Ca2+-dependent pathway, to trigger exocytotic secretion. However, little is currently known about the mechanism by which this may occur. Here we show the key signaling pathway that mediates GTP-dependent exocytosis. Incubation of permeabilized PC12 cells with soluble RalA GTPase, but not RhoA or Rab3A GTPases, strongly inhibited GTP-dependent exocytosis. A Ral-binding fragment from Sec5, a component of the exocyst complex, showed a similar inhibition. Point mutations in both RalA (RalA(E38R)) and the Sec5 (Sec5(T11A)) fragment, which abolish RalA-Sec5 interaction also abolished the inhibition of GTP-dependent exocytosis. Moreover, transfection with wild-type RalA, but not RalA(E38R), enhanced GTP-dependent exocytosis. In contrast the RalA and the Sec5 fragment showed no inhibition of Ca2+-dependent exocytosis, but cleavage of a SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein by Botulinum neurotoxin blocked both GTP- and Ca2+-dependent exocytosis. Our results indicate that the interaction between RalA and the exocyst complex (containing Sec5) is essential for GTP-dependent exocytosis. Furthermore, GTP- and Ca2+-dependent exocytosis use different sensors and effectors for triggering exocytosis whereas their final fusion steps are both SNARE-dependent.
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RalA regulates vesicle tethering and fusion through interacting with exocyst.
“Ralbp1 binds to RalA, a small GTPase regulating vesicle tethering and fusion through interacting with exocyst (11, 20, 41–44).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [42]
The Abstract reports that RalA interacts with the exocyst and that this interaction is essential for GTP-dependent exocytosis in PC12 cells. It does not establish that RalA regulates vesicle tethering specifically, and it says how the interaction communicates with SNAREs to trigger membrane fusion remains to be determined. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRalbp1 binds to RalA.
“Ralbp1 binds to RalA, a small GTPase regulating vesicle tethering and fusion through interacting with exocyst (11, 20, 41–44).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [42]
The Results section describes RalA binding to Sec5, an exocyst component, but does not identify Sec5 as Ralbp1. Searches for RalBP1, Ral binding protein 1, and RLIP76 found no passage in our copy addressing whether Ralbp1 binds RalA; no page number was available. (LLM, conf=0.73)
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Research works printed but not linked: 3
- [1]1. Gomperts, B.D. Nature. 1983; 306:64-66 Crossref Scopus (266) PubMed Google Scholar
- [2]2. Fernandez, J.M. ∙ Neher, E. ∙ Gomperts, B.D. Nature. 1984; 312:453-455 Crossref Scopus (402) PubMed Google Scholar
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Ral mediates activity‐dependent growth of postsynaptic membranes via recruitment of the exocyst
Teodoro, R. O., Pekkurnaz, G., Nasser, A., Higashi‐Kovtun, M. E., Balakireva, M., McLachlan, I. G., Camonis, J., & Schwarz, T. L. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.147 · Cited by 61 · see citing works
Krause, G. J., Diaz, A., Jafari, M., Khawaja, R. R., Agullo‐Pascual, E., Santiago‐Fernández, O., Richards, A. L., Chen, K., Dmitriev, P., Sun, Y., et al. (2022) · Aging Cell · doi:10.1111/acel.13713 · Cited by 35 · see citing works
Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module
Wang, S., Chen, X., Crisman, L., Dou, X., Winborn, C. S., Wan, C., Puscher, H., Yin, Q., Kennedy, M. J., & Shen, J. (2023) · Science Advances · doi:10.1126/sciadv.ade2540 · Cited by 14 · see citing works
- Authors
- Wang, L., Li, G., & Sugita, S.
- Affiliations
- University Health Network (CA)
- Corresponding author
- Sugita, Shuzo
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-05
- Volume
- 279
- Issue
- 19
- Pages
- 19875-19881
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2031494860
- Cited by
- 68
- References
- 0
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 1 · 2021: 1 · 2020: 2 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 1 · 2013: 6 · 2012: 2
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- RalA, exocyst complex, Sec5, secretory cells, SNARE proteins, botulinum toxin, PC12 cells, GTPase signaling, membrane fusion
- MeSH terms
- Animals, Botulinum Toxins, Calcium, Dose-Response Relationship, Drug, Exocytosis, Glutathione Transferase, Guanosine Triphosphate, Immunohistochemistry, Magnesium, Membrane Proteins, Microscopy, Fluorescence, Neurons, Plasmids, Protein Binding, Recombinant Proteins, Growth Hormone, Transfection, Mutagenesis, Site-Directed, PC12 Cells, Point Mutation, Microscopy, Confocal, GTP Phosphohydrolases, ral GTP-Binding Proteins, Guanine Nucleotide Dissociation Inhibitors, rhoA GTP-Binding Protein, rab3A GTP-Binding Protein, Vesicular Transport Proteins, SNARE Proteins, Rats, rho-Specific Guanine Nucleotide Dissociation Inhibitors
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