Phorbolester-activated Munc13-1 and ubMunc13-2 exert opposing effects on dense-core vesicle secretion.
| Autor: | Houy S; Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark., Martins JS; Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark., Lipstein N; Department of Molecular Neurobiology, Max-Planck-Institute for Multidisciplinary Sciences, Göttingen, Germany.; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany., Sørensen JB; Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark. |
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| Jazyk: | angličtina |
| Zdroj: | ELife [Elife] 2022 Oct 10; Vol. 11. Date of Electronic Publication: 2022 Oct 10. |
| DOI: | 10.7554/eLife.79433 |
| Abstrakt: | Munc13 proteins are priming factors for SNARE-dependent exocytosis, which are activated by diacylglycerol (DAG)-binding to their C1-domain. Several Munc13 paralogs exist, but their differential roles are not well understood. We studied the interdependence of phorbolesters (DAG mimics) with Munc13-1 and ubMunc13-2 in mouse adrenal chromaffin cells. Although expression of either Munc13-1 or ubMunc13-2 stimulated secretion, phorbolester was only stimulatory for secretion when ubMunc13-2 expression dominated, but inhibitory when Munc13-1 dominated. Accordingly, phorbolester stimulated secretion in wildtype cells, or cells overexpressing ubMunc13-2, but inhibited secretion in Munc13-2/ Unc13b knockout (KO) cells or in cells overexpressing Munc13-1. Phorbolester was more stimulatory in the Munc13-1/ Unc13a KO than in WT littermates, showing that endogenous Munc13-1 limits the effects of phorbolester. Imaging showed that ubMunc13-2 traffics to the plasma membrane with a time-course matching Ca 2+ -dependent secretion, and trafficking is independent of Synaptotagmin-7 (Syt7). However, in the absence of Syt7, phorbolester became inhibitory for both Munc13-1 and ubMunc13-2-driven secretion, indicating that stimulatory phorbolester x Munc13-2 interaction depends on functional pairing with Syt7. Overall, DAG/phorbolester, ubMunc13-2 and Syt7 form a stimulatory triad for dense-core vesicle priming. Competing Interests: SH, JM, NL, JS No competing interests declared (© 2022, Houy, Martins et al.) |
| Databáze: | MEDLINE |
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