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Munc13-4 functions as a Ca 2+ sensor for homotypic secretory granule fusion to generate endosomal exocytic vacuoles.
- Source :
-
Molecular biology of the cell [Mol Biol Cell] 2017 Mar 15; Vol. 28 (6), pp. 792-808. Date of Electronic Publication: 2017 Jan 18. - Publication Year :
- 2017
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Abstract
- Munc13-4 is a Ca <superscript>2+</superscript> -dependent SNARE (soluble N -ethylmaleimide-sensitive factor attachment protein receptor)- and phospholipid-binding protein that localizes to and primes secretory granules (SGs) for Ca <superscript>2+</superscript> -evoked secretion in various secretory cells. Studies in mast cell-like RBL-2H3 cells provide direct evidence that Munc13-4 with its two Ca <superscript>2+</superscript> -binding C2 domains functions as a Ca <superscript>2+</superscript> sensor for SG exocytosis. Unexpectedly, Ca <superscript>2+</superscript> stimulation also generated large (>2.4 μm in diameter) Munc13-4 <superscript>+</superscript> /Rab7 <superscript>+</superscript> /Rab11 <superscript>+</superscript> endosomal vacuoles. Vacuole generation involved the homotypic fusion of Munc13-4 <superscript>+</superscript> /Rab7 <superscript>+</superscript> SGs, followed by a merge with Rab11 <superscript>+</superscript> endosomes, and depended on Ca <superscript>2+</superscript> binding to Munc13-4. Munc13-4 promoted the Ca <superscript>2+</superscript> -stimulated fusion of VAMP8-containing liposomes with liposomes containing exocytic or endosomal Q-SNAREs and directly interacted with late endosomal SNARE complexes. Thus Munc13-4 is a tethering/priming factor and Ca <superscript>2+</superscript> sensor for both heterotypic SG-plasma membrane and homotypic SG-SG fusion. Total internal reflection fluorescence microscopy imaging revealed that vacuoles were exocytic and mediated secretion of β-hexosaminidase and cytokines accompanied by Munc13-4 diffusion onto the plasma membrane. The results provide new molecular insights into the mechanism of multigranular compound exocytosis commonly observed in various secretory cells.<br /> (© 2017 Woo et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)
- Subjects :
- Animals
Calcium metabolism
Carrier Proteins metabolism
Cell Line
Endosomes metabolism
Endosomes physiology
Exocytosis physiology
Membrane Fusion physiology
Protein Transport
Proteins genetics
Rats
SNARE Proteins metabolism
Secretory Vesicles physiology
Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins metabolism
Vacuoles physiology
Proteins metabolism
Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1939-4586
- Volume :
- 28
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecular biology of the cell
- Publication Type :
- Academic Journal
- Accession number :
- 28100639
- Full Text :
- https://doi.org/10.1091/mbc.E16-08-0617